The oxytocin-CD38-vitamin A axis in pregnant women involves both hypothalamic and placental regulation.

OBJECTIVE: Oxytocin, a hypothalamic hormone secreted upon release of ectoenzyme CD38, plays a vital role in interpersonal bonding behaviors. Reduced plasma oxytocin characterizes autistic individuals. CD38 levels, which were found to be low in LBCs derived from autistic patients, is upregulated upon the addition of a vitamin A derivative. During pregnancy, oxytocin is also secreted by placenta. Recent controversial studies have suggested an increased risk for autism when oxytocin is used during induction and augmentation of labor. We aimed to examine the tripartite relationship between oxytocin, CD38 and vitamin A in pregnant women and their newborns. METHODS: Thirty-one healthy expectant mothers were enlisted for this study. Levels of oxytocin, CD38 and ATRA were measured in both maternal peripheral and newborn cord blood, and the tripartite relationship between these parameters examined. Estrogen and progesterone levels of the mothers were also recorded. Several clinical measures were also noted. RESULTS: Mean maternal oxytocin and vitamin A levels were approximately 8- and 4-fold higher, respectively, than neonatal levels. CD38 expression, however, was 9 times higher in neonates than in the maternal group. Positive correlation was found between maternal and cord blood for both oxytocin and CD38. CONCLUSIONS: This establishment of normative values for oxytocin, CD38 and vitamin A in healthy pregnant women and newborns may serve as a reference in the investigation of developing pathologies of disorders such as autism.

Association between the oxytocin receptor (OXTR) gene and autism: relationship to Vineland Adaptive Behavior Scales and cognition.

Evidence both from animal and human studies suggests that common polymorphisms in the oxytocin receptor (OXTR) gene are likely candidates to confer risk for autism spectrum disorders (ASD). In lower mammals, oxytocin is important in a wide range of social behaviors, and recent human studies have shown that administration of oxytocin modulates behavior in both clinical and non-clinical groups. Additionally, two linkage studies and two recent association investigations also underscore a possible role for the OXTR gene in predisposing to ASD. We undertook a comprehensive study of all 18 tagged SNPs across the entire OXTR gene region identified using HapMap data and the Haploview algorithm. Altogether 152 subjects diagnosed with ASDs (that is, DSM IV autistic disorder or pervasive developmental disorder--NOS) from 133 families were genotyped (parents and affected siblings). Both individual SNPs and haplotypes were tested for association using family-based association tests as provided in the UNPHASED set of programs. Significant association with single SNPs and haplotypes (global P-values <0.05, following permutation test adjustment) were observed with ASD. Association was also observed with IQ and the Vineland Adaptive Behavior Scales (VABS). In particular, a five-locus haplotype block (rs237897-rs13316193-rs237889-rs2254298-rs2268494) was significantly associated with ASD (nominal global P=0.000019; adjusted global P=0.009) and a single haplotype (carried by 7% of the population) within that block showed highly significant association (P=0.00005). This is the third association study, in a third ethnic group, showing that SNPs and haplotypes in the OXTR gene confer risk for ASD. The current investigation also shows association with IQ and total VABS scores (as well as the communication, daily living skills and socialization subdomains), suggesting that this gene shapes both cognition and daily living skills that may cross diagnostic boundaries.

Association between the arginine vasopressin 1a receptor (AVPR1a) gene and autism in a family-based study: mediation by socialization skills.

We examined three microsatellites in the arginine vasopressin 1a receptor gene (AVPR1a), two in the promoter region (RS1 and RS3) and an intronic microsatellite (AVR), for association with autism as well as scores on the Vineland Adaptive Behavior Scale (VABS), the Autism Diagnostic Interview-Revised (ADI-R) and the Autism Diagnostic Observation Scale-Generic (ADOS-G), measures that are widely used to diagnose autism spectrum disorders. We tested for association between the AVPR1a microsatellites and autism in 116 families (128 probands diagnosed with the ADI-R and ADOS-G using a family-based association test (UNPHASED)). Testing each individual microsatellite showed significant transmission disequilibrium in these families with the AVR intronic microsatellite (UNPHASED: LRS=11.46, global P-value=0.009, df=3). Haplotype analysis of three microsatellites also showed significant association (LRS=144.94, df=103, global P=0.004). Additionally, significant association is observed between these three microsatellite haplotypes and the VABS scores (P=0.009), with the ADI-R (P=0.009) and the ADOS-G (P=0.0000765) diagnoses of autistic disorder versus pervasive developmental disorder-not otherwise specified (PDD-NOS) that were available for 47 of these probands. This is the third consecutive report of an association between the AVPR1a gene and autism spectrum disorders and in the current study a third microsatellite is shown to be associated with autism spectrum disorders as well as haplotypes consisting of all three markers. Importantly, the association appears to be mainly mediated by the role of the AVPR1a gene in shaping socialization skills, similar to its role in lower vertebrates.Molecular Psychiatry (2006) 11, 488-494. doi:10.1038/sj.mp.4001812; published online 7 March 2006.

Evidence for an association with the serotonin transporter promoter region polymorphism and autism.

We have examined three functional polymorphisms, serotonin transporter promoter region polymorphism (5-HTTLPR), dopamine D4 exon III repeat region (DRD4), and catechol-O-methyltransferase (COMT), in a small family-based design toward identifying candidate genes that confer risk for autism. A significant excess of the long/long 5-HTTLPR genotype was observed (likelihood ratio = 7.18; P = 0.027; 2 df; n = 33 families) as well as preferential transmission of the long allele of the 5-HTTLPR (TDT chi-square = 5.44; P<0.025; 1 df). No association was observed between the COMT and DRD4 polymorphisms and autism in this sample. Some previous studies have observed linkage between autism and the 5-HTTLPR polymorphism and the current results are similar to those first reported by Klauck et al. [1997: Hum Genet 100:224-229; 1997: Hum Mol Genet 6:2233-2238]. Additionally, elevated serotonin levels have been consistently found in 30%-50% of autistic patients and may represent a marker for familial autism. Hyperserotonemia in autism appears to be due to enhanced 5-HT uptake, as free 5-HT levels are normal and the current report of an excess of the long/long 5-HTTLPR genotype in autism could provide a partial molecular explanation for high platelet serotonin content in autism.

Maternal versus nonmaternal care and seven domains of children's development.

A series of meta-analyses was conducted on findings from 59 studies to examine the linkage between maternal versus nonmaternal care, 7 indices of child behavior, and 10 potential moderators. Results indicate that children receiving nonmaternal care do not differ from children receiving maternal care on any of the 7 indices. Year of publication and psychometrics of outcome index were found to moderate the linkage between maternal versus nonmaternal care and attachment classification and between maternal versus nonmaternal care and child adjustment, respectively. Examination of the simultaneous impact of extent of care and age of entry on attachment behaviors revealed the moderating impact of the latter. Although it cannot be concluded that nonmaternal care has no impact on children, most of the analyses suggest that in and of itself, or in interaction with one factor at a time, nonmaternal care does not affect child development.

Theory of mind abilities of children with schizophrenia, children with autism, and normally developing children.

Theory of mind (ToM) abilities of children with schizophrenia, children with high functioning autism, and normally developing children, matched on mental age (MA), verbal MA, and performance MA, were compared. Both clinical groups were matched on chronological age as well, whereas the normally developing children were younger. A fact belief task, a value belief task, a deception task, and a false belief task were administered. The three groups did not differ on the fact belief task. Children with autism performed more poorly than normally developing children on value belief and false belief tasks, and more poorly than individuals with schizophrenia on the deception task. Children with schizophrenia performed more poorly than normally developing children only on the false belief task. Overall, the group with autism passed significantly fewer tasks compared to the normally developing group. ToM abilities correlated with verbal abilities for individuals with autism. The ToM abilities of children with paranoid schizophrenia and children with undifferentiated or disorganized schizophrenia did not differ. Findings strengthen the notion of a limited understanding of ToM in schizophrenia, and support the notion that ToM deficits, although more severe in autism, are not unique to autism.

Mother-infant affect synchrony as an antecedent of the emergence of self-control.

This study examined relations between mother-infant affect synchrony and the emergence of children's self-control. Mother-infant face-to-face play and infant difficult temperament were examined at 3 and 9 months. Maternal and infant affective states at play were coded in 0.25-s frames, and synchrony was computed with cross-correlation functions. Self-control, verbal IQ, and maternal warm discipline were assessed at 2 years. Maternal synchrony with infant affect at 3 months (infant-leads-mother-follows relation) and mutual synchrony at 9 months (cross-dependence between maternal and infant affect) were each related to self-control at 2 years when temperament, IQ, and maternal style were partialed. Infant temperament moderated the relations of synchrony and self-control, and closer associations were found between mutual synchrony and self-control for difficult infants. Shorter lags to maternal synchrony at 3 months were independently related to self-control. The mutual regulation of affect in infancy, as moderated by temperament, is proposed as an important contributor to the emergence of self-regulation.

Meta-analyses comparing theory of mind abilities of individuals with autism, individuals with mental retardation, and normally developing individuals.

A deficit in theory of mind (ToM) abilities has been described as the core deficit in autism. The authors performed 3 meta-analyses, comparing ToM abilities of individuals with autism, individuals with mental retardation (MR), and normally developing individuals. Results indicated that individuals with autism and MR have impaired ToM abilities. The etiology associated with MR (i.e., Down syndrome, undifferentiated etiology) was found to be an important moderator variable. Chronological age (CA) and verbal mental age (VMA) of the normally developing children and CA, VMA, and performance mental age of individuals with MR, and type of matching between the groups were also found to be moderator variables. Discussion focuses on the implication of the findings and emphasizes the need to consider the specific etiology of comparison groups when studying abilities and impairments of individuals with autism and MR.

The Autism Diagnostic Interview-Revised and the Childhood Autism Rating Scale: differences between diagnostic systems and comparison between genders.

Diagnoses for autism based on the Autism Diagnostic Interview-Revised (ADI-R) and the Childhood Autism Rating Scale (CARS) were examined for 83 individuals with suspected autism. Agreement between systems reached 85.7%. Participants receiving diagnosis of autism based on only one system were significantly younger in age than individuals receiving diagnoses according to both systems. Individuals who did not receive diagnosis of autism on the ADI-R had lower chronological and mental ages and lower CARS scores compared to individuals who received diagnosis of autism based on the ADI-R. Eighteen females and 18 males were matched to examine possible gender differences. No significant findings were revealed, suggesting that the symptoms of autism according to the ADI-R and CARS do not differ between males and females when matched for chronological and mental ages.

Theory of mind abilities in individuals with autism, Down syndrome, and mental retardation of unknown etiology: the role of age and intelligence.

We examined theory of mind abilities of individuals with autism, mental retardation (MR) of unknown etiology, Down syndrome, and normal children. On false belief and deception tasks, normal children performed better than all clinical groups, while no differences emerged among the clinical groups. The groups with MR performed better than the group with autism on the value task only. For individuals with autism, theory of mind abilities correlated with verbal ability. For individuals with MR nonverbal abilities correlated with deception and false belief scores. Findings are discussed in terms of the specificity of the theory of mind deficit to autism.

Seriation, conservation, and theory of mind abilities in individuals with autism, individuals with mental retardation, and normally developing children.

Seriation, conservation, and theory of mind abilities were examined in individuals with autism (N = 16), mental retardation (N = 16), and in normally developing children (N = 16). Seriation tasks included seriation of tubes, blocks, and flat squares. Conservation tasks included conservation of area, number, substance, quantity, and weight. Theory of mind tasks involved predicting false belief and understanding value and fact beliefs. Participants with autism performed better than participants with mental retardation on seriation, while no differences emerged between these groups on conservation and false belief. Individuals with autism performed less well than individuals with mental retardation on the value and fact belief tasks; however, when verbal ability was held as a covariant, the difference was no longer significant. Normally developing children performed better than the other two groups on all tasks. These results suggest that autism does not involve a specific impairment in theory of mind and that theory of mind deficits are not unique to autism.

From categorization to classification: a comparison among individuals with autism, mental retardation, and normal development.

Free-sorting, matrix, and class-inclusion tasks were administered to 16 participants with autism, 16 participants with mental retardation (MR), and 16 normal children, matched for mental age. On perceptual matrices, participants with MR performed less well than those with autism, who performed less well than normal children. On functional matrices, participants with autism and those with MR performed less well than normal children. Participants with autism performed less well than participants with MR and normal children in free-sorting representational objects and in the class-inclusion tasks, which require higher operational thought. These results suggest that individuals with autism have difficulties with tasks that necessitate internal manipulation of information. This impairment is discussed in relation to the cognitive deficit characterizing autism.

Comparison between diagnostic instruments for identifying high-functioning children with autism.

Two instruments for identifying autism in children and adolescents with intellectual abilities in the normal range were compared. Diagnostic tools consisted of the Autism Behavior Checklist (ABC) and the Autism Diagnostic Interview (ADI). The sample was composed of 18 children who were all diagnosed as having either infantile autism or infantile autism, residual state based on DSM-III criteria by a clinical team using observations, parental interviews, and interactions with the children. Only 4 of the children met diagnostic cutoffs for autism on the current ABC but all met criteria for diagnosis on the ABC using parental recall of the child's behavior at 3-5 years of age. The ADI had somewhat greater specificity in that 3 children did not meet criteria for diagnosis although 2 of these children also received ABC scores based on parental recollection that were in the borderline range.

Parental perception of emotional expressiveness in children with autism.

Parents' perceptions of their children's emotional expressiveness, and possible bases for these perceptions, were investigated in a study comparing older, nonretarded autistic and normal children and in another study comparing young autistic, mentally retarded, and normal children. Both groups of autistic children were perceived as showing more negative emotion and less positive emotion than comparison children. In the younger sample, parental perceptions correlated with the children's attention and responsiveness to others' displays of emotion in 2 laboratory situations. Findings contradict the view that autism involves the "absence of emotional reaction" (American Psychiatric Association, 1987, p. 35).

Understanding of simple and complex emotions in non-retarded children with autism.

Non-retarded autistic children are compared to normal controls on measures of emotion expression and recognition. In general, autistic subjects recounted appropriate examples of simple and complex emotions, and accurately labeled relatively ambiguous affect expression in pictures. Autistic children manifested some difficulty talking about socially derived emotions, pride and embarrassment. They required more time and more prompts, their responses were more tentative and "scripted", and they displayed limited understanding of the salience of others in embarrassing situations. Results are discussed in relation to theory of mind impairment and compensation strategies in autism.

Responses to the negative emotions of others by autistic, mentally retarded, and normal children.

Attention, facial affect, and behavioral responses to adults showing distress, fear, and discomfort were compared for autistic, mentally retarded, and normal children. The normal and mentally retarded children were very attentive to adults in all 3 situations. In contrast, many of the autistic children appeared to ignore or not notice the adults showing these negative affects. As a group, the autistic children looked at the adults less and were much more engaged in toy play than the other children during periods when an adult pretended to be hurt. The autistic children were also less attentive to adults showing fear, although their behavior was not different from the normal children. Few of the children in any group showed much facial affect in response to these situations. The results are discussed in terms of the importance of affect in the social learning experiences of the young child.

Empathy and cognition in high-functioning children with autism.

This study compares the ability of nonretarded autistic children (9-16 years of age) with the ability of normally developing children (9-14 years of age) to discriminate between various emotional states, to take the perspective of another regarding emotional states, and to respond affectively. The children's understanding of conservation was also assessed. While the children with autism did surprisingly well on the empathy-related measures, they performed less well than the normal children on these measures and on conservation. There was a closer association between cognitive abilities and affective understanding in the group of autistic children than in the control group.

Affect and attention in children with Down syndrome.

The association of the affective responsiveness and attention regulation with communication and language skills of children with Down syndrome was examined. Results both replicate and extend previous research on the attentional and affective characteristics of children with Down syndrome. These children tended to look more often to the face of the social partner but less often to nonfocal toys. They also tended to shift affect expressions more frequently but did not differ from MA-matched nonretarded children in overall durations of affect. The association of these variables with communication and language indicated that the more positive affect displayed toward people and the shorter the average looks to the partner's face, the higher the verbal language skills of young children with Down syndrome.