Carl Feinstein

Plasma oxytocin levels in autistic children.

BACKGROUND Social impairments are central to the syndrome of autism. The neuropeptide oxytocin (OT) has been implicated in the regulation of social behavior in animals but has not yet been examined in autistic subjects. METHODS To determine whether autistic children have abnormalities in OT, midday plasma samples from 29 autistic and 30 age-matched normal children, all prepubertal, were analyzed by radioimmunoassay for levels of OT. RESULTS Despite individual variability and overlapping group distributions, the autistic group had significantly lower plasma OT levels than the normal group. OT increased with age in the normal but not the autistic children. Elevated OT was associated with higher scores on social and developmental measures for the normal children, but was associated with lower scores for the autistic children. These relationships were strongest in a subset of autistic children identified as aloof. CONCLUSIONS Although making inferences to central OT functioning from peripheral measurement is difficult, the data suggest that OT abnormalities may exist in autism, and that more direct investigation of central nervous system OT function is warranted.

Oxytocin and autistic disorder: alterations in peptide forms

BACKGROUND Oxytocin (OT) is synthesized as a prohormone that is sequentially processed to peptides. These peptides are the bioactive amidated form (OT) and the C-terminal extended peptides, OT-Gly, OT-Gly-Lys and OT-Gly-Lys-Arg, which are designated together as OT-X. As an extension of our previous study finding decreased plasma OT in autism, studies were conducted to determine whether there were changes in OT peptide forms in autistic children. METHODS Twenty eight male subjects (97 +/- 20 months; range, 70-139 months), diagnosed with DSM-IV autistic disorder through observation and semi-structured interview, were compared with 31 age-matched nonpsychiatric control subjects (106 +/- 22 months; range, 74-140 months). Using OT antisera with different specificity for the peptide forms, we measured plasma OT and OT-X in each group. RESULTS T tests showed that there was a decrease in plasma OT (t = 4.4, p <.0001), an increase in OT-X (t = 2.3, p <.03) and an increase in the ratio of OT-X/OT (t = 4.5, p <.0001) in the autistic sample, compared with control subjects. CONCLUSIONS The results suggest that children with autistic disorder show alterations in the endocrine OT system. Deficits in OT peptide processing in children with autism may be important in the development of this syndrome.

COMT genotype predicts longitudinal cognitive decline and psychosis in 22q11.2 deletion syndrome

Although schizophrenia is strongly hereditary, there are limited data regarding biological risk factors and pathophysiological processes. In this longitudinal study of adolescents with 22q11.2 deletion syndrome, we identified the catechol-O-methyltransferase low-activity allele (COMTL) as a risk factor for decline in prefrontal cortical volume and cognition, as well as for the consequent development of psychotic symptoms during adolescence. The 22q11.2 deletion syndrome is a promising model for identifying biomarkers related to the development of schizophrenia.

Salience Network–Based Classification and Prediction of Symptom Severity in Children With Autism

IMPORTANCE Autism spectrum disorder (ASD) affects 1 in 88 children and is characterized by a complex phenotype, including social, communicative, and sensorimotor deficits. Autism spectrum disorder has been linked with atypical connectivity across multiple brain systems, yet the nature of these differences in young children with the disorder is not well understood. OBJECTIVES To examine connectivity of large-scale brain networks and determine whether specific networks can distinguish children with ASD from typically developing (TD) children and predict symptom severity in children with ASD. DESIGN, SETTING, AND PARTICIPANTS Case-control study performed at Stanford University School of Medicine of 20 children 7 to 12 years old with ASD and 20 age-, sex-, and IQ-matched TD children. MAIN OUTCOMES AND MEASURES Between-group differences in intrinsic functional connectivity of large-scale brain networks, performance of a classifier built to discriminate children with ASD from TD children based on specific brain networks, and correlations between brain networks and core symptoms of ASD. RESULTS We observed stronger functional connectivity within several large-scale brain networks in children with ASD compared with TD children. This hyperconnectivity in ASD encompassed salience, default mode, frontotemporal, motor, and visual networks. This hyperconnectivity result was replicated in an independent cohort obtained from publicly available databases. Using maps of each individuals salience network, children with ASD could be discriminated from TD children with a classification accuracy of 78%, with 75% sensitivity and 80% specificity. The salience network showed the highest classification accuracy among all networks examined, and the blood oxygen-level dependent signal in this network predicted restricted and repetitive behavior scores. The classifier discriminated ASD from TD in the independent sample with 83% accuracy, 67% sensitivity, and 100% specificity. CONCLUSIONS AND RELEVANCE Salience network hyperconnectivity may be a distinguishing feature in children with ASD. Quantification of brain network connectivity is a step toward developing biomarkers for objectively identifying children with ASD.

Executive Functioning in High-functioning Children with Autism

Executive functioning was investigated in 34 children (24 boys and 10 girls) with developmental language disorder (DLD) and 21 children (18 boys and 3 girls) with high-functioning autistic disorder (HAD) matched on Full Scale IQ, Nonverbal IQ, age (mean age 9 year, 1 month), and SES. The DLD group had a Verbal IQ that was 10 points higher than the HAD group. These children were given the Wisconsin Card Sorting Test (WCST), the Mazes subtest from the WISC-R, the Underlining test, and the Rapid Automatized Naming test. In addition, these children were given the Vineland Scales of Adaptive Functioning and the Wing Diagnostic Symptom Checklist in order to assess severity of autistic symptomatology. Results indicated that the only significant difference between the two groups on the cognitive tasks was perseverative errors on the WCST; there was no significant difference on total number of categories achieved or total number of errors on the WCST or on the other executive function measures. There was also significant overlap in the scores between the two groups and the difference in perseverative errors was no longer significant when Verbal IQ was partialled out. Executive functioning was strongly related to all IQ variables in the DLD group and particularly related to Verbal IQ in the HAD group. Although there was a relationship in the HAD group between executive functioning and adaptive functioning, as well as between executive functioning and autistic symptomatology, these relationships were generally no longer significant in the HAD group after the variance due to Verbal IQ was accounted for. The results are interpreted to indicate that although impaired executive functioning is a commonly associated feature of autism, it is not universal in autism and is unlikely to cause autistic behaviors or deficits in adaptive function.

Psychiatric disorders and behavioral problems in children with Velocardiofacial syndrome: Usefulness as phenotypic indicators of schizophrenia risk

BACKGROUND Velocardiofacial syndrome (VCFS), a genetic deletion condition with numerous cognitive sequelae, is associated with a high rate of psychiatric disorders in childhood. More recently, VCFS has been identified as a high-risk factor for developing adult onset schizophrenia. However, it has never been demonstrated that the childhood psychiatric disorders found in children with VCFS differ from those found in children with a similar degree of cognitive impairment. Identification of a specific behavioral (psychiatric) phenotype in childhood VCFS offers the potential for elucidating the symptomatic precursors of adult onset schizophrenia. METHODS Twenty-eight children with VCFS and 29 age- and cognitively matched control subjects received a standardized assessment of childhood psychiatric disorders and behaviors measured by the Child Behavior Checklist (CBCL). Findings from the two groups were compared. RESULTS The rates and types of psychiatric disorder and behavior problems in VCFS and cognitively matched control subjects were very high, but showed no significant differences. CONCLUSIONS Psychopathology in children with VCFS may not differ from that found in cognitively matched control subjects. Another explanation is that subtle phenotypic differences in behavior found in VCFS can not be observed using standard symptom inventories. The high rate of psychopathology in children with VCFS is not a useful phenotypic indicator of high risk for adult onset schizophrenia.

Subgroups of Children With Autism by Cluster Analysis: A Longitudinal Examination

OBJECTIVES A hierarchical cluster analysis was conducted using a sample of 138 school-age children with autism. The objective was to examine (1) the characteristics of resulting subgroups, (2) the relationship of these subgroups to subgroups of the same children determined at preschool age, and (3) preschool variables that best predicted school-age functioning. METHOD Ninety-five cases were analyzed. RESULTS Findings support the presence of 2 subgroups marked by different levels of social, language, and nonverbal ability, with the higher group showing essentially normal cognitive and behavioral scores. The relationship of high- and low-functioning subgroup membership to levels of functioning at preschool age was highly significant. CONCLUSIONS School-age functioning was strongly predicted by preschool cognitive functioning but was not strongly predicted by preschool social abnormality or severity of autistic symptoms. The differential outcome of the 2 groups shows that high IQ is necessary but not sufficient for optimal outcome in the presence of severe language impairment.

Autism: the point of view from fragile X studies.

The relationship between the fragile X syndrome (FXS) and autism is reviewed. Shortly after the FXS was first described, it was noted that certain behaviors commonly found in afflicted individuals resemble certain features of autism. Research concerning a possible relationship between these conditions is summarized. The outcome of this research indicates that FXS is not a common cause of autism, although the number of individuals with FXS who meet diagnostic criteria for autism is higher than can be accounted for by chance. The major focus of this paper highlights that FXS is a well-defined neurogenetic disease that includes a cognitive behavioral phenotype, and has both a known biological cause and an increasing well-delineated pathogenesis. Autism is a behaviorally defined syndrome whose syndromic boundaries and biological causes are not known. These profound differences complicate comparisons and causal discussions. However, the behavioral neurogenetic information available about FXS suggests certain pathways for future research directed at elucidating the syndrome of autism.

Diagnosis and classification in autism.

This study compared four systems for the diagnosis of autism (DSM-III, DSM-III-R, DSM-IV, and ICD-10) with two empirically derived taxa of autism, and with three social subgroups of autism (Aloof, Passive, and Active-but-Odd) in 194 preschool children with salient social impairment. There were significant behavior and IQ differences between autistic and other-PDD groups for all four diagnostic systems, and a significant association was found (a) for Taxon B, diagnoses of autism, and the Aloof subgroup, and (b) for Taxon A, other-PDD, and the Active-but-Odd subgroup. Findings offer support for two major overlapping continua within idiopathic Pervasive Developmental Disorder.

Psychotic symptoms in children and adolescents with 22q11.2 deletion syndrome: Neuropsychological and behavioral implications.

Individuals with 22q11.2 deletion syndrome (22q11DS) are at increased risk for developing schizophrenia: half of affected adolescents report transient psychotic experiences and up to 30% of adults are diagnosed with schizophrenia. Prospective studies have shown that psychotic symptoms in childhood are predictive of later schizophreniform disorders. The current study aimed to define the prevalence and correlates of psychotic symptoms (PS) in young children and adolescents with 22q11DS. Forty-three children and adolescents with 22q11DS (mean age = 10.62+/-11.19) participated in this study. The occurrence of PS and their neuropsychological and behavioral correlates were investigated through semi-structured interviews and standardized measures. Psychotic symptoms were reported in 28% of the total sample and 17% of pre-adolescent children, and associated with decreased verbal IQ scores [F(1) = 4.41, p = 0.042]. Compared to young patients without PS, young patients with PS were perceived by their parents as more anxious-depressed [F(1) = 4.76, p = 0.035] and withdrawn [F(1) = 7.63, p = 0.009], with reduced adaptive socialization skills [F(1) = 6.88, p = 0.012]. Results suggest that psychotic manifestations are present earlier than typically reported in youngsters with 22q11DS and are accompanied by reduced verbal IQ performance and decreased adaptative social skills. The symptomatic, neuropsychological and behavioral characteristics observed in the current study may constitute central markers of increased risk for psychosis in 22q11DS.