A short-term longitudinal study of correlates and sequelae of attachment security in autism.

In this short-term longitudinal study, 30 preschool-aged children with autism were first observed in Ainsworth's Strange Situation Procedure and, separately, interacting with the primary caregiver in the home. One year later, each child completed both a developmental assessment and an observational assessment of empathic responding. Behaviors typical for children with autism were distinguished from behaviors suggestive of relationally based attachment disorganization. Forty-five percent of the children were classified as securely attached. The secure group demonstrated language skills superior to those of the insecurely attached group, concurrently and during the follow-up. Compared to parents of children who were insecurely attached, parents of securely attached children were rated as more sensitive. Compared to both organized insecure and disorganized children, secure children were rated as more responsive to an examiner's apparent distress during the follow-up relative to their ratings at intake, whereas empathy ratings of children with insecure classifications did not increase. Importantly, attachment security was associated with empathy above and beyond the contribution of children's language level. These results indicate that the sequelae of attachment security in autism may be similar to those documented for typically developing children.

Child-mother attachments in the face of grandparent HIV.

Child-mother attachment, as observed in the Strange Situation (SSP), was assessed in 61 families affected by HIV and 18 neighborhood comparison families not affected by HIV, but of similar ethnicity and socioeconomic status. Children were aged one to three years at the assessment. Secure attachment was significantly less likely among children in the HIV-affected group than among comparison group children (36% versus 67%). The most common pattern of attachment in the HIV-affected group was disorganized/disoriented, observed in 41% of children (versus 22% of comparison children). Children from families that included a surviving grandparent with HIV showed disorganized attachments more often than children whose grandparents died (53% versus 36%). Child attachment classifications were not associated with families' participation in a family-based, cognitive-behavioral HIV intervention. These results document the inter-generational impact of young mothers' who were growing up with an HIV-infected parent. These findings suggest that families affected by HIV may benefit from interventions that address attachment issues.

Common genetic variants on 5p14.1 associate with autism spectrum disorders.

Autism spectrum disorders (ASDs) represent a group of childhood neurodevelopmental and neuropsychiatric disorders characterized by deficits in verbal communication, impairment of social interaction, and restricted and repetitive patterns of interests and behaviour. To identify common genetic risk factors underlying ASDs, here we present the results of genome-wide association studies on a cohort of 780 families (3,101 subjects) with affected children, and a second cohort of 1,204 affected subjects and 6,491 control subjects, all of whom were of European ancestry. Six single nucleotide polymorphisms between cadherin 10 (CDH10) and cadherin 9 (CDH9)-two genes encoding neuronal cell-adhesion molecules-revealed strong association signals, with the most significant SNP being rs4307059 (P = 3.4 x 10(-8), odds ratio = 1.19). These signals were replicated in two independent cohorts, with combined P values ranging from 7.4 x 10(-8) to 2.1 x 10(-10). Our results implicate neuronal cell-adhesion molecules in the pathogenesis of ASDs, and represent, to our knowledge, the first demonstration of genome-wide significant association of common variants with susceptibility to ASDs.

Genome-wide analyses of exonic copy number variants in a family-based study point to novel autism susceptibility genes.

The genetics underlying the autism spectrum disorders (ASDs) is complex and remains poorly understood. Previous work has demonstrated an important role for structural variation in a subset of cases, but has lacked the resolution necessary to move beyond detection of large regions of potential interest to identification of individual genes. To pinpoint genes likely to contribute to ASD etiology, we performed high density genotyping in 912 multiplex families from the Autism Genetics Resource Exchange (AGRE) collection and contrasted results to those obtained for 1,488 healthy controls. Through prioritization of exonic deletions (eDels), exonic duplications (eDups), and whole gene duplication events (gDups), we identified more than 150 loci harboring rare variants in multiple unrelated probands, but no controls. Importantly, 27 of these were confirmed on examination of an independent replication cohort comprised of 859 cases and an additional 1,051 controls. Rare variants at known loci, including exonic deletions at NRXN1 and whole gene duplications encompassing UBE3A and several other genes in the 15q11-q13 region, were observed in the course of these analyses. Strong support was likewise observed for previously unreported genes such as BZRAP1, an adaptor molecule known to regulate synaptic transmission, with eDels or eDups observed in twelve unrelated cases but no controls (p = 2.3x10(-5)). Less is known about MDGA2, likewise observed to be case-specific (p = 1.3x10(-4)). But, it is notable that the encoded protein shows an unexpectedly high similarity to Contactin 4 (BLAST E-value = 3x10(-39)), which has also been linked to disease. That hundreds of distinct rare variants were each seen only once further highlights complexity in the ASDs and points to the continued need for larger cohorts.

Response to distress in infants at risk for autism: a prospective longitudinal study.

BACKGROUND: Infants and preschoolers with ASD show impairment in their responses to other people's distress relative to children with other developmental delays and typically developing children. This deficit is expected to disrupt social interactions, social learning, and the formation of close relationships. Response to distress has not been evaluated previously in infants with ASD earlier than 18 months of age. METHODS: Participants were 103 infant siblings of children with autism and 55 low-risk controls. All children were screened for ASD at 36 months and 14 were diagnosed with ASD. Infants' responsiveness to distress was evaluated at 12, 18, 24, and 36 months. An examiner pretended to hit her finger with a toy mallet and infants' responses were video-recorded. Attention to the examiner and congruent changes in affect were coded on four-point Likert scales. RESULTS: Cross-sectional and longitudinal analyses confirm that the ASD group paid less attention and demonstrated less change in affect in response to the examiner's distress relative to the high-risk and low-risk participants who were not subsequently diagnosed with ASD. Group differences remained when verbal skills and general social responsiveness were included in the analytic models. CONCLUSIONS: Diagnostic groups differ on distress response from 12 to 36 months of age. Distress-response measures are predictive of later ASD diagnosis above and beyond verbal impairments. Distress response is a worthwhile target for early intervention programs.

Understanding emotions in others: mirror neuron dysfunction in children with autism spectrum disorders.

To examine mirror neuron abnormalities in autism, high-functioning children with autism and matched controls underwent fMRI while imitating and observing emotional expressions. Although both groups performed the tasks equally well, children with autism showed no mirror neuron activity in the inferior frontal gyrus (pars opercularis). Notably, activity in this area was inversely related to symptom severity in the social domain, suggesting that a dysfunctional 'mirror neuron system' may underlie the social deficits observed in autism.

Mothers' narratives regarding their child with autism predict maternal synchronous behavior during play.

BACKGROUND: Mothers' synchronous playtime behaviors have been linked to language development in children with autism (Siller & Sigman, 2002, 2008). This study sought to explain individual differences in maternal synchrony in order to improve parent-training programs targeting communication skills in children with autism. METHODS: Participants were 67 children with autism under the age of 7 and their biological mothers. Maternal cognitions were assessed using two narrative measures, the Insightfulness Assessment (Koren-Karie & Oppenheim, 1997) and the Reaction to Diagnosis Interview (Pianta & Marvin, 1992). Mean levels of maternal synchrony, measured with a micro-analytic coding system (Siller & Sigman, 2002, 2008), were compared between groups formed according to mothers' interview classifications. RESULTS: Variation in maternal synchrony was related to classification of the Insightfulness Assessment, but not the Reaction to Diagnosis Interview. Child characteristics were not related to interview classifications or ratings of maternal synchrony. CONCLUSION: Qualities of mothers' narratives about their child with autism and the relationship with the child are associated with variability in maternal synchronous behavior during play.

Dietary micronutrients are associated with higher cognitive function gains among primary school children in rural Kenya.

With the exception of iodine and Fe, there is still very limited information on the effect of micronutrients on cognitive function, especially among school-age children. The present analysis evaluates the relationship between dietary Fe, Zn and B vitamins (B12, B6, folate and riboflavin) and gains in cognitive test scores among school children in rural Kenya. Data for the present study were obtained from The Child Nutrition Kenya Project, a 2-year longitudinal, randomised controlled feeding intervention study using animal source foods. Dietary nutrient values were based on monthly and bimonthly 24 h recall data collected during the study period. In longitudinal regression analyses, available Fe, available Zn, vitamin B12 and riboflavin showed significant relationships with improved cognitive test scores, after controlling for confounders such as energy intake, school, socio-economic status and morbidity. Available Fe intake was associated with significantly higher gains in Raven's Coloured Progressive Matrices test scores over time. Available Zn intake was associated with significantly higher gains in digit span-total test scores over time, while vitamin B12 and riboflavin intakes were each associated with significantly higher gains in digit span-forward test scores over time. This analysis demonstrates the influence of improved dietary micronutrient status on school children's cognitive function.

One-year follow-up of family versus child CBT for anxiety disorders: Exploring the roles of child age and parental intrusiveness.

OBJECTIVE: To compare the relative long-term benefit of family-focused cognitive behavioral therapy (FCBT) and child-focused cognitive behavioral therapy (CCBT) for child anxiety disorders at a 1-year follow-up. METHOD: Thirty-five children (6-13 years old) randomly assigned to 12-16 sessions of family-focused CBT (FCBT) or child-focused CBT (CCBT) participated in a 1-year follow-up assessment. Independent evaluators, parents, and children rated anxiety and parental intrusiveness. All were blind to treatment condition and study hypotheses. RESULTS: Children assigned to FCBT had lower anxiety scores than children assigned to CCBT on follow-up diagnostician- and parent-report scores, but not child-report scores. Exploratory analyses suggested the advantage of FCBT over CCBT may have been evident more for early adolescents than for younger children and that reductions in parental intrusiveness may have mediated the treatment effect. CONCLUSION: FCBT may yield a stronger treatment effect than CCBT that lasts for at least 1 year, although the lack of consistency across informants necessitates a circumspect view of the findings. The potential moderating and mediating effects considered in this study offer interesting avenues for further study.

Multiple forms of atypical rearrangements generating supernumerary derivative chromosome 15.

BACKGROUND: Maternally-derived duplications that include the imprinted region on the proximal long arm of chromosome 15 underlie a complex neurobehavioral disorder characterized by cognitive impairment, seizures and a substantial risk for autism spectrum disorders1. The duplications most often take the form of a supernumerary pseudodicentric derivative chromosome 15 [der(15)] that has been called inverted duplication 15 or isodicentric 15 [idic(15)], although interstitial rearrangements also occur. Similar to the deletions found in most cases of Angelman and Prader Willi syndrome, the duplications appear to be mediated by unequal homologous recombination involving low copy repeats (LCR) that are found clustered in the region. Five recurrent breakpoints have been described in most cases of segmental aneuploidy of chromosome 15q11-q13 and previous studies have shown that most idic(15) chromosomes arise through BP3:BP3 or BP4:BP5 recombination events. RESULTS: Here we describe four duplication chromosomes that show evidence of atypical recombination events that involve regions outside the common breakpoints. Additionally, in one patient with a mosaic complex der(15), we examined homologous pairing of chromosome 15q11-q13 alleles by FISH in a region of frontal cortex, which identified mosaicism in this tissue and also demonstrated pairing of the signals from the der(15) and the normal homologues. CONCLUSION: Involvement of atypical BP in the generation of idic(15) chromosomes can lead to considerable structural heterogeneity.

Reading affect in the face and voice: neural correlates of interpreting communicative intent in children and adolescents with autism spectrum disorders.

CONTEXT: Understanding a speaker's communicative intent in everyday interactions is likely to draw on cues such as facial expression and tone of voice. Prior research has shown that individuals with autism spectrum disorders (ASD) show reduced activity in brain regions that respond selectively to the face and voice. However, there is also evidence that activity in key regions can be increased if task demands allow for explicit processing of emotion. OBJECTIVES: To examine the neural circuitry underlying impairments in interpreting communicative intentions in ASD using irony comprehension as a test case, and to determine whether explicit instructions to attend to facial expression and tone of voice will elicit more normative patterns of brain activity. DESIGN, SETTING, AND PARTICIPANTS: Eighteen boys with ASD (aged 7-17 years, full-scale IQ >70) and 18 typically developing (TD) boys underwent functional magnetic resonance imaging at the Ahmanson-Lovelace Brain Mapping Center, University of California, Los Angeles. MAIN OUTCOME MEASURES: Blood oxygenation level-dependent brain activity during the presentation of short scenarios involving irony. Behavioral performance (accuracy and response time) was also recorded. RESULTS: Reduced activity in the medial prefrontal cortex and right superior temporal gyrus was observed in children with ASD relative to TD children during the perception of potentially ironic vs control scenarios. Importantly, a significant group x condition interaction in the medial prefrontal cortex showed that activity was modulated by explicit instructions to attend to facial expression and tone of voice only in the ASD group. Finally, medial prefrontal cortex activity was inversely related to symptom severity in children with ASD such that children with greater social impairment showed less activity in this region. CONCLUSIONS: Explicit instructions to attend to facial expression and tone of voice can elicit increased activity in the medial prefrontal cortex, part of a network important for understanding the intentions of others, in children with ASD. These findings suggest a strategy for future intervention research.

Frontal contributions to face processing differences in autism: evidence from fMRI of inverted face processing.

Functional neuroimaging studies of face processing deficits in autism have typically focused on visual processing regions, such as the fusiform face area (FFA), which have shown reduced activity in autism spectrum disorders (ASD), though inconsistently. We recently reported reduced activity in the inferior frontal region in ASD, implicating impaired mirror-neuron systems during face processing. In the present study, we used fMRI during a face processing task in which subjects had to match faces presented in the upright versus inverted position. Typically developing (TD) children showed a classic behavioral inversion effect, increased reaction time for inverted faces, while this effect was significantly reduced in ASD subjects. The fMRI data showed similar responses in the fusiform face area for ASD and TD children, with both groups demonstrating increased activation for inverted faces. However, the groups did differ in several brain regions implicated in social cognition, particularly prefrontal cortex and amygdala. These data suggest that the behavioral differences in processing upright versus inverted faces for TD children are related not to visual information processing but to the social significance of the stimuli. Our results are consistent with other recent studies implicating frontal and limbic dysfunction during face processing in autism.

Modeling longitudinal change in the language abilities of children with autism: parent behaviors and child characteristics as predictors of change.

The objective of the current study was to evaluate the patterns of longitudinal change in the language abilities of 28 children with autism during early and middle childhood. Results from fitting a series of multilevel models showed that children's rate of language growth was independently predicted by (a) children's responsiveness to others' bids for joint attention and (b) parents' responsiveness to their children's attention and activity during play. Both predictive relations could not be explained by initial variation in global developmental characteristics, such as IQ, mental age, or language abilities. These findings support a social?pragmatic view on language acquisition, which emphasizes the collaborative process through which children and their parents negotiate shared meaning.

Evidence for latent classes of IQ in young children with autism spectrum disorder.

Autism is currently viewed as a spectrum condition that includes strikingly different severity levels; IQ is consistently described as one of the primary aspects of the heterogeneity in autism. To investigate the possibility of more than one distinct subtype of autism based on IQ both latent class analysis and taxometrics methods were used to classify Mullen IQs in a sample of 456 children with autism spectrum disorder. We found evidence for multiple IQbased subgroups using both methods. Groups differed in level of intellectual functioning and patterns of verbal versus nonverbal ability. Results support the notion of distinct subtypes of autism that differ in severity of intellectual ability, patterns of cognitive strengths and weaknesses, and severity of autism symptoms.

A prospective study of response to name in infants at risk for autism.

OBJECTIVE: To assess the sensitivity and specificity of decreased response to name at age 12 months as a screen for autism spectrum disorders (ASD) and other developmental delays. DESIGN: Prospective, longitudinal design studying infants at risk for ASD. SETTING: Research laboratory at university medical center. PARTICIPANTS: Infants at risk for autism (55 six-month-olds, 101 twelve-month-olds) and a control group at no known risk (43 six-month-olds, 46 twelve-month-olds). To date, 46 at-risk infants and 25 control infants have been followed up to 24 months. Intervention Experimental task eliciting response-to-name behavior. MAIN OUTCOME MEASURES: Autism Diagnostic Observation Schedule, Mullen Scales of Early Learning. RESULTS: At age 6 months, there was a nonsignificant trend for control infants to require a fewer number of calls to respond to name than infants at risk for autism. At age 12 months, 100% of infants in the control group "passed," responding on the first or second name call, while 86% in the at-risk group did. Three fourths of children who failed the task were identified with developmental problems at age 24 months. Specificity of failing to respond to name was 0.89 for ASD and 0.94 for any developmental delay. Sensitivity was 0.50 for ASD and 0.39 for any developmental delay. CONCLUSIONS: Failure to respond to name by age 12 months is highly suggestive of developmental abnormality but does not identify all children at risk for developmental problems. Lack of responding to name is not universal among infants later diagnosed with ASD and/or other developmental delays. Poor response to name may be a trait of the broader autism phenotype in infancy.

Neural basis of irony comprehension in children with autism: the role of prosody and context.

While individuals with autism spectrum disorders (ASD) are typically impaired in interpreting the communicative intent of others, little is known about the neural bases of higher-level pragmatic impairments. Here, we used functional MRI (fMRI) to examine the neural circuitry underlying deficits in understanding irony in high-functioning children with ASD. Participants listened to short scenarios and decided whether the speaker was sincere or ironic. Three types of scenarios were used in which we varied the information available to guide this decision. Scenarios included (i) both knowledge of the event outcome and strong prosodic cues (sincere or sarcastic intonation), (ii) prosodic cues only or (iii) knowledge of the event outcome only. Although children with ASD performed well above chance, they were less accurate than typically developing (TD) children at interpreting the communicative intent behind a potentially ironic remark, particularly with regard to taking advantage of available contextual information. In contrast to prior research showing hypoactivation of regions involved in understanding the mental states of others, children with ASD showed significantly greater activity than TD children in the right inferior frontal gyrus (IFG) as well as in bilateral temporal regions. Increased activity in the ASD group fell within the network recruited in the TD group and may reflect more effortful processing needed to interpret the intended meaning of an utterance. These results confirm that children with ASD have difficulty interpreting the communicative intent of others and suggest that these individuals can recruit regions activated as part of the normative neural circuitry when task demands require explicit attention to socially relevant cues.

The development of young siblings of children with autism from 4 to 54 months.

Cognitive and language skills of 39 siblings of children with autism (SIBS-A) and 39 siblings of typically developing children (SIBS-TD) at ages 4, 14, 24, 36, and 54 months were compared. Twelve of the 39 SIBS-A revealed a delay in cognition and/or language (including one child diagnosed with autism) compared to only two SIBS-TD. Developmental trajectories revealed that the cognitive differences disappeared by age 54 months, but some differences in language ability remained. Thus, most SIBS-A were well-functioning, but some revealed cognitive and/or language difficulties during the preschool years. Even these siblings by and large caught up by the age of 54 months, with receptive and expressive language abilities remaining an area of difficulty for some earlier identified siblings.

Cognitive and verbal abilities of 24- to 36-month-old siblings of children with autism.

The cognitive and language skills of 30 siblings of children with autism (SIBS-A) and 30 siblings of typically developing children (SIBS-TD) were compared. Non-significant group differences emerged for cognition at both ages. At 24 months, significantly more SIBS-A demonstrated language scores one or two standard deviations below the mean compared to SIBS-TD. At 36 months, the groups differed significantly in receptive language, and more SIBS-A displayed receptive and expressive difficulties compared to SIBS-TD. Six SIBS-A (including one diagnosed with autism) revealed language scores more than two standard deviations below the mean at both ages, a pattern not seen in the SIBS-TD. Results are discussed in reference to language difficulties in autism spectrum disorders and the genetic liability for autism.

Studying the emergence of autism spectrum disorders in high-risk infants: methodological and practical issues.

Detecting early signs of autism is essential for timely diagnosis and initiation of effective interventions. Several research groups have initiated prospective studies of high-risk populations including infant siblings, to systematically collect data on early signs within a longitudinal design. Despite the potential advantages of prospective studies of young children at high-risk for autism, there are also significant methodological, ethical and practical challenges. This paper outlines several of these challenges, including those related to sampling (e.g., defining appropriate comparison groups), measurement and clinical implications (e.g., addressing the needs of infants suspected of having early signs). We suggest possible design and implementation strategies to address these various challenges, based on current research efforts in the field and previous studies involving high-risk populations.

Family cognitive behavioral therapy for child anxiety disorders.

OBJECTIVE: This study compared family-focused cognitive behavioral therapy (CBT; the Building Confidence Program) with traditional child-focused CBT with minimal family involvement for children with anxiety disorders. METHOD: Forty clinically anxious youth (6-13 years old) were randomly assigned to a family- or child-focused cognitive-behavioral therapy (CBT). Conditions were matched for therapist contact time. Both interventions included coping skills training and in vivo exposure, but the family CBT intervention also included parent communication training. Independent evaluator, parent, and child report measures with demonstrated validity and reliability were used to assess child anxiety symptom outcomes at pre- and posttreatment. The data analytic strategy involved an evaluable patient analysis. RESULTS: Compared with child-focused CBT, family CBT was associated with greater improvement on independent evaluators' ratings and parent reports of child anxiety--but not children's self-reports--at posttreatment. CONCLUSIONS: Both treatment groups showed improvement on all outcome measures, but family CBT may provide additional benefit over and above child-focused CBT. These findings provide preliminary support for the efficacy of the "Building Confidence" program and encourage further research in parental participation in treatment for childhood anxiety.