Psychodynamic and behavior modification approaches to the treatment of infantile autism

In the treatment of infantile autism, behaviorists emphasize directed behavioral change while psychodynamic therapists tend to focus attention on the worker-child relationship. A review of the literature suggests that both of these aspects of intervention are important, and that both play a role in virtually all therapeutic efforts. The similarities in methods of intervention found in the work of investigators of very different theoretical persuasion raise the possibility that most treatment methods owe more to empirical clinical experience than to their presumed derivation from a theoretical model. This thesis is further examined with respect to a 50-year-old case history by Lightmer Witmer, and the work of the present writer with an 11-year-old autistic boy.Special thanks are due to Master Teacher Nancy Buckler whose insights and suggestions greatly contributed to the treatment approach adopted by the author.     

Cerebral asymmetry and the development of early infantile autism

Two experiments involving listening preferences of autistic and normal subjects were conducted to test the hypothesis that the right cerebral hemisphere is more active than the left hemisphere in autistic children. Results showed that when given a choice between verbal and musical material, the autistic children preferred music, while normal children showed no preference. Secondly, autistic children listened to both types of material predominantly with the left ear. Although normal subjects showed greater variation among themselves, they tended to listen to music more often with the left ear and to listen to verbal material more often with the right. These results support the notion that some autistic children are predominantly righthemisphere processors.This research was supported in part by a Minor Research Grant and a Summer Stipend from the Faculty of Arts, York University. Parts of this material have been presented at the 1977 meetings of the Society for Research in Child Development and the National Conference of the Canadian Society for Autistic Children. The author wishes to thank Patricia Crawford, Peter Morden, Susan B. Sussman, and Reva Tankle for their invaluable assistance on this project.     

Variables relating to the mental development of children with infantile autism

Among 54 variables studied in 194 autistic children, nine variables--meaningful words, pointing, eating without assistance, crane symptoms (maneuvers of letting a person manipulate an object by grasping his or her hand and bringing it close to the object), echolalia, changing clothes without assistance, speech loss (loss of once-emerged meaningful words before 30 months of age), establishment of toilet-training and diagnosis of MBD--were correlated significantly to the children's mental development levels with absolute values of Kendall's tau b over 0.2. A discriminant analysis showed that three positive correlates, i.e., meaningful words, pointing and echolalia, and a negative correlate, i.e., crane symptoms, were important in distinguishing between young autistics with and without unfavorable mental development and possible poor outcomes.     

The effect of age on concentrations of monoamines, amino acids, and their related substances in the cerebrospinal fluid

Summary In 24 h reserpine-treated mice, the locomotion induced by the D₁ dopamine agonist SKF 38393 (30 mg/kg IP) was facilitated by the NMDA antagonists MK 801 (0.4 mg/kg IP), CPP (1 mg/kg IP), CGP 40116 (1 mg/kg IP) and HA 966 (2 mg/kg IP), and by the AMPA antagonist NBQX (0.2 mg/kg IP). By contrast, CPP, CGP 40116 and NBQX had no effect on, while MK 801 and HA 966 suppressed, the locomotion elicited by the selective D₂ agonist RU 24213 (5 mg/kg SC). When these same doses of glutamate antagonists were tested against the locomotion induced by a threshold (0.025 mg/kg SC), intermediate (0.1 mg/kg SC) or large dose (0.5 mg/kg SC) of the mixed D₁/D₂ agonist apomorphine, CPP, CGP 40116 and HA 966 were found to have no significant effect, whilst MK 801 was strongly inhibitory and NBQX potentiated the response to 0.1 mg/kg apomorphine only. It is evident from these data that the behavioural interaction profiles between glutamate antagonists and dopamine agonists are complex and depend on the receptor selectivities of the drugs concerned. The manner of the interaction between these glutamate antagonists and selective D₁ or D₂ agonists, is not predictive of the way that blockade of glutamate transmission interferes with the actions of drugs which have combined D₁ and D₂ motor stimulant properties.     

Intrinsic and extrinsic determinants of neuronal development: Relation to infantile autism

This paper attempts to view the autistic syndrome in the context of a disorder of brain development. The authors review some of the known or suspected causes of the autistic syndrome: maternal rubella, metabolic diseases, and heredity. Some basic principles of cellular neuroanatomy and chemical neurotransmission are sketched. The stages of human brain development from neurulation through histogenesis, cell migration, and elaboration of dendritic trees and axonal projections are described. The authors conclude that there are a limited number of developmental loci that could be disrupted and lead to the autistic syndrome, and that these most probably occur in the end stages of neuronal development, after the migrating neurons have reached their final place in the brain and have begun to elaborate communicative processes. Finally, the authors speculate on how neurochemical disturbances might alter end stage neuronal differentiation leading to the pathology of infantile autism.The authors wish to express their gratitude to Rebecca and Solomon Baker for support of the studies on autistic children ongoing in the Division of Child Psychiatry and Child Development. The first author is the recipient of a Research Career Development Award (Type II) from the NIMH (MH 00219). The second author is the recipient of a Neuropathology Research Training Grant (NS 07111) from the NINCDS.     

Age changes in concentrations of monoamines and related substances in the cerebrospinal fluid]

We studied age changes of concentrations of thirteen substances including monoamines, their precursors and metabolites in the cerebrospinal fluid, using high performance liquid chromatography. Cerebrospinal fluid was obtained from 106 subjects without neurological diseases (44.2 +/- 17.3 years) who underwent minor operations under lumbar anesthesia. Concentrations of dopamine, norepinephrine, tyrosine and 3-methoxy-4-hydroxy-phenylalanine were significantly increased with age, while concentrations of other monoamine precursors and metabolites were unchanged. There was a significant positive correlation between concentrations of the following substances: dopamine and norepinephrine; tyrosine and tryptophan; tyrosine and 3-methoxy-4-hydroxy-phenylalanine; tyrosine and 5-hydroxytryptophan; homovanillic acid and 5-hydroxyindoleacetic acid. Norepinephrine concentrations were positively correlated with concentrations of 3-methoxy-4-hydroxy-phenylglycol, whereas dopamine concentrations were not with homovanillic acid concentrations. The significance of these results was discussed with regard to age changes of transmitter secretion and metabolism, the binding capacity of receptors and cerebrospinal fluid kinetics of the measured substances.     

Investigation of whole blood and urine monoamines in autism

Levels of serotonin (5-HT), dopamine (DA), norepinephrine (NE) and epinephrine (E) were determined in the whole blood and urine of 23 children with autism and compared to those of normal children. Very significant group effects (low whole blood 5-HT, high urinary 5-HT and high NE+E in autism) and age effects (urinary 5-HT and DA decrease with age) were found. Moreover, the urinary DA and the whole blood E levels were correlated with clinical findings. The results suggest a maturation defect of noradrenergic systems, possibly disturbed dopaminergic and serotoninergic metabolism, and a functional imbalance among these neurotransmitters in autism.

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Zusammenfassung Es wurden die Spiegel für Serotonin (5-HT), Dopamin (DA), Noradrenalin (NA) und Adrenalin (A) im Blut und Urin für 23 Kinder mit frühkindlichem Autismus bestimmt und mit den Werten normaler Kinder verglichen. Es ergaben sich sehr signifikante Gruppeneffekte (niedrige Blutspiegel für 5-HT, hohe Urinspiegel für 5-HT und hohes NA plus A bei Kindern mit Autismus) und Alterseffekte (Abnahme mit zunehmendem Alter für Urinspiegel 5-HT und DA). Darüber hinaus waren die Urinspiegel für DA und Blutspiegel für A mit klinischen Befunden korreliert. Die Ergebnisse legen nahe, daß beim frühkindlichen Autismus ein Reifungsdefizit des noradrenergen Systems, möglicherweise auch ein gestörter dopaminerger und serotonerger Stoffwechsel und ein funktionelles Ungleichgewicht dieser Neurotransmitter vorliegt.

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Résumé Les taux de sérotonine (5-HT), de dopamine (DA), de norépinéphrine (NE) et d'épinéphrine (E) ont été déterminés sur des prélèvements d'urine et de sang chez 23 enfants autistes comparés à des enfants normaux. Des effets très significatifs pour les groupes (taux bas de 5-HT sanguins, taux élevés de 5-HT et de NE+E urinaire) et pour les âges (taux urinaires de 5-HT et de DA diminuant avec l'âge) ont été observés. De plus, les taux urinaires de DA et les taux sanguins de E sont corrélés avec les évaluations cliniques. Les résultats suggèrent un trouble de la maturation du système noradrénergique avec une perturbation possible du métabolisme dopaminergique et sérotoninergique, et un mauvais fonctionnement dans l'équilibre de ces neurotransmetteurs dans l'autisme.

     

Prospective preliminary analysis of the development of autism and epilepsy in children with infantile spasms

The objective of this study was to compare the efficacy of corticotropin (ACTH) versus vigabatrin in treating infantile spasms and to determine which medication has a more favorable long-term outcome in terms of cognitive function, evolution of epilepsy, and incidence of autism. Patients with infantile spasms were included in the study if they were 3 to 16 months old, had hypsarrhythmia, and had no previous treatment with vigabatrin or corticosteroids. Patient evaluation included electroencephalographic and psychometric measures before and after treatment. Patients were stratified based on etiology (idiopathic or symptomatic) and sex and then randomized between the ACTH and vigabatrin treatment groups. Each of the treatment groups received either ACTH or vigabatrin for 2 weeks. At the end of 2 weeks of treatment, patients were considered responders if spasms and hypsarrhythmia resolved. Nonresponders were crossed over and treated with the alternate drug. Nine patients were included in the study. Three patients received ACTH, one of whom was a responder. Six patients received vigabatrin, three of whom were responders. The five nonresponders received both therapies. All patients had some degree of developmental plateau or regression before the initiation of treatment. Four patients with idiopathic infantile spasms showed improved cognitive function following treatment. The remaining five patients remained significantly delayed. Five patients with symptomatic infantile spasms had epilepsy following treatment; three of them were in the autistic spectrum. The small number of infants in this pilot study is insufficient to determine which of the two drugs is more effective. However, the following trends were identified: vigabatrin may be more effective for patients with symptomatic infantile spasms; patients with idiopathic infantile spasms tend to have a better cognitive outcome; and patients with symptomatic infantile spasms tend to develop both epilepsy and autism.     

Haloperidol in the treatment of infantile autism: effects on learning and behavioral symptoms

In this double-blind, placebo-controlled study the administration of haloperidol resulted in significant decreases in behavioral symptoms and in general clinical improvement in 40 autistic children ages 2.33 to 6.92 years. Haloperidol also produced greater facilitation and retention of discrimination learning in the laboratory. No adverse effects were observed at therapeutic doses, which ranged from 0.5 to 3.0 mg/day or 0.019 to 0.217 mg/kg per day.     

Inhibition of protein and aminoacyl-tRNA synthesis, and binding and transport sites for aromatic amino acids in the brain in vitro with aromatic acids

The influx of [3H]phenylalanine, [3H]tyrosine and [3H]tryptophan into brain slices and synaptosomes, their binding to synaptic membranes and their incorporation into protein and aminoacyl-tRNA were studied in the presence of an excess of a second aromatic amino acid or some other aromatic acid, viz., phenylpyruvate, phenyllactate, phenylacetate, homogentisate, salicylate or benzoate. The influx into brain slices was strongly inhibited by a second aromatic amino acid and in general also by phenylpyruvate and homogentisate, but the effects of these substances upon the influx into synaptosomes were slight. The binding of phenylalanine and tyrosine to the synaptic membranes was affected mainly by phenylpyruvate and homogentisate, and these were also effective in preventing the formation of aminoacyl-tRNA, and thus apparently inhibited the biosynthesis of proteins and polyphenylalanine. In all cases phenyllactate, phenylacetate salicylate and benzoate had virtually no effect. Phenylalanine seemed to be a noncompetitive, and tyrosine a competitive inhibitor, while tryptophan had both properties, as was also the case with phenylpyruvate and homogentisate. Under phenylketonuric conditions high excesses of phenylalanine and phenylpyruvate, and also certain other aromatic compounds, seemed to occupy the cellular transport sites for amino acids on the cellular membranes and prevent the formation of aminoacyl-tRNAs, thus inhibiting brain protein synthesis. The reduced supply of intracellular amino acids and the inhibition of protein synthesis may constitute one reason for the development of biochemical phenylketonuric abnormalities.     

Fenfluramine treatment in infantile autism. Neurochemical, electrophysiological, and behavioral effects

As part of a multicenter, collaborative project, response to fenfluramine was assessed in 10 autistic outpatients. After 4 months of treatment, blood serotonin concentrations decreased an average of 60 per cent and returned to pretreatment levels after 2 months on placebo. This reduction was accompanied by a decrease in certain behavioral symptoms, including motor activity, distractibility, and mood disturbances. Baseline evoked potential recordings indicated that autistic patients tended to have a larger amplitude of the P3 component to frequent tones as compared to age-matched controls. A tendency toward "normalization" of the P3 effect was observed during the medication trial and during the final placebo period. Treatment response was not related to initial serotonin levels, and no major clinical side effects were associated with fenfluramine.