Ditza A. Zachor

Accelerated maturation of white matter in young children with autism: A high b value DWI study

The goal of this work was to study white matter maturation in young children with autism following previous reports of increased cerebral volume during early development, as well as arguments for abnormal neural growth patterns and regulation at this critical developmental period. We applied diffusion tensor imaging (DTI) and high b value diffusion-weighted imaging (DWI) to young children diagnosed with autism and to a typically developing (TD) control group. Fractional anisotropy (FA), probability and displacement were measured in overall analysis as well as in regions of interest (ROI). Individual data points of children with autism were compared to the developmental curves obtained from typically developing children. Increased restriction, reflected in significantly increased FA and probability along with reduced displacement values, was detected in overall analysis as well as in several brain regions. Increased restriction, suggesting an early and accelerated abnormal maturation of white matter, was more dominant in the left hemisphere and was mainly detected in the frontal lobe. No changes were detected in the occipital lobes. These results support previous claims of abnormal brain overgrowth in young children with autism and are in contrast to the decreased restricted diffusion reported in previous studies in adolescent with autism.

Abnormal White Matter Integrity in Young Children with Autism

This study investigated white matter integrity in young children with autism using diffusion tensor imaging (DTI). Twenty‐two children with autism, mean age 3:2 years, and 32 controls, mean age 3:4 years, participated in the study. Tract‐based spatial statistics (TBSS) revealed white matter abnormalities in several distinct clusters within the genu and body of the corpus callosum (CC), left superior longitudinal fasciculus (SLF) and right and left cingulum (Cg). TBSS–VOIs analysis was performed in the clusters where differences in fractional anisotropy (FA) were detected to investigate the relationship between changes in FA and diffusivity indices. In all VOIs, increase in FA was caused by a decrease in radial diffusivity (Dr), while no changes in axial diffusivity (Da) or mean diffusivity (MD) were observed. Tractography analysis was applied to further study the CC, SLF, and Cg. Witelson parcellation scheme was used for the CC. Significant increase in FA was seen in children with autism in the mid‐body of the CC as well as in the left Cg. It is suggested that such abnormal white matter integrity in young children with autism may adversely affect connectivity between different brain regions and may be linked to some of the behavioral impairments apparent in autism. Hum Brain Mapp, 2011.

Immunological and autoimmune considerations of Autism Spectrum Disorders

Autism Spectrum Disorders (ASD) are a group of heterogeneous neurodevelopmental conditions presenting in early childhood with a prevalence ranging from 0.7% to 2.64%. Social interaction and communication skills are impaired and children often present with unusual repetitive behavior. The condition persists for life with major implications for the individual, the family and the entire health care system. While the etiology of ASD remains unknown, various clues suggest a possible association with altered immune responses and ASD. Inflammation in the brain and CNS has been reported by several groups with notable microglia activation and increased cytokine production in postmortem brain specimens of young and old individuals with ASD. Moreover several laboratories have isolated distinctive brain and CNS reactive antibodies from individuals with ASD. Large population based epidemiological studies have established a correlation between ASD and a family history of autoimmune diseases, associations with MHC complex haplotypes, and abnormal levels of various inflammatory cytokines and immunological markers in the blood. In addition, there is evidence that antibodies that are only present in some mothers of children with ASD bind to fetal brain proteins and may be a marker or risk factor for ASD. Studies involving the injection of these ASD specific maternal serum antibodies into pregnant mice during gestation, or gestational exposure of Rhesus monkeys to IgG subclass of these antibodies, have consistently elicited behavioral changes in offspring that have relevance to ASD. We will summarize the various types of studies associating ASD with the immune system, critically evaluate the quality of these studies, and attempt to integrate them in a way that clarifies the areas of immune and autoimmune phenomena in ASD research that will be important indicators for future research.

Assisted reproductive technology and risk for autism spectrum disorder

Epidemiologic studies on maternal and pregnancy risk factors for autism spectrum disorder (ASD), including use of assisted reproductive technology (ART), found conflicting results. This study included the following aims: to assess frequencies of ART in a large ASD group; to examine confounding birth and familial risk factors in the ASD with ART group; to examine possible relationships between ART and autism severity, adaptive skills and developmental trajectory. The study included 624 participants, 507 diagnosed with ASD. Autism severity and adaptive skills were assessed using standardized tests. Extensive medical, familial and developmental histories were obtained. The rate of ART in the ASD group was significantly higher (10.7%) than in a large Israeli population (3.06%). Parental ages distribution did not differ in both ASD groups, with and without ART. Although maternal age was more advanced in the ASD group, the frequency of ART in young mothers (<29 years) was still significantly high (8.7%). The frequencies of gestational age <36 weeks and low birth weight (<2500 g) in the ASD with ART singleton group and in the Israeli population were not significantly different. None of the ASD with ART group and 14.7% in the ASD without ART group had a relative with ASD. Autism severity, adaptive skills and developmental regression were not significantly different in the ASD with and without ART groups. This pilot study points to the role of assisted conception as a risk factor for ASD. However, this group of ASD with ART does not represent a separate clinical phenotype in ASD.

Cross-cultural differences in comorbid symptoms of children with autism spectrum disorders: An international examination between Israel, South Korea, the United Kingdom and the United States of America

Objective: To examine the relationship between culture and symptoms of comorbid psychopathology in those with autism spectrum disorders (ASD). Design: Multivariate analyses of variance (MANOVAs) for each country and each sub-scale of the Autism Spectrum Disorders-Comorbid for Children (ASD-CC). Follow-up independent univariate analyses and post-hoc tests as needed. Methods: Separate samples from South Korea, the UK and Israel were compared to a sample from the US in order to examine cultural contributions, using the ASD-CC. Results: Overall, few differences were found. Significantly, the US had significantly higher scores than South Korea on the avoidant sub-scale. Additionally, the US had significantly higher scores than Israel on the over-eating and tantrum sub-scales. No significant differences were found between the US and the UK. Conclusion: Cultural factors, such as views of typical behaviour, should be taken into account when examining symptoms of comorbidity in children with ASD.

CYP2D6 genotyping in paediatric patients with autism treated with risperidone: a preliminary cohort study

To evaluate the association between cytochrome P450 2D6 (CYP2D6) phenotypes in paediatric patients with autistic spectrum disorders (ASD) treated with risperidone, adverse drug reactions (ADRs), and drug efficacy.

Specific Neurological Phenotypes in Autism Spectrum Disorders Are Associated with Sex Representation

Autism spectrum disorder (ASD) is a heritable disorder occurring predominantly in males. The aim of this study was to compare sex differences in the prevalence of specific neurological phenotypes commonly described in ASD. The study included 663 participants, aged 18 months to 15 years, diagnosed with ASD. Neurological and behavioral assessments were performed using standardized tests, and obtaining medical, developmental, and familial histories from the parents. Phenotypes under investigation were macro‐ and microcephaly, developmental regression, minor neurological and musculoskeletal deficits (MNMD), and seizures. Male : female ratio in the ASD group was 6.7:1. No sex differences in autism severity, cognitive ability, and adaptive functioning were noted. Mean head circumference percentile for males (50.1 ± 25.6) was significantly larger than females (43.4 ± 30.2). Micro‐ and macrocephaly were more frequent in ASD than expected (5.9%; 18.1%, respectively). Microcephaly in females (15.1%) was significantly more prevalent than in males (4.5%). The prevalence of macrocephaly in both sexes did not differ significantly. Regression was noted in 30.2% of the females with ASD, significantly higher than in males (18.9%). MNMD was documented in 73.8% of the females, significantly higher than in males (57.1%). M:F ratio decreased in a group with two or more phenotypes (3.6:1), while male predominance was more significant in the group without phenotypes (13.6:1). Neurological phenotypes associated with ASD are more prevalent in females than in males, resulting in more complex clinical and neurological manifestations in females. Therefore, involvement of different etiologies is suggested in ASD in females. Autism Res 2013, 6: 596–604.

Recommendations for early diagnosis and intervention in autism spectrum disorders: An Italian–Israeli consensus conference

On April 2013 experts in the field of autism from Italy and Israel convened in Jerusalem to discuss and finalize clinical recommendations for early diagnosis and intervention in Autism Spectrum Disorders (ASDs). In this paper, we summarize the results of this Italian-Israeli consensus conference. ASDs constitute a class of severe and heterogeneous neurodevelopmental conditions caused by atypical brain development beginning during early prenatal life, reflecting many genetic, neurobiological and environmental influences. The first clinical signs of ASDs begin to be evident in children between 12 and 18 months of age, often after a period of relatively typical postnatal development. Recent longitudinal studies reveal substantial diversity in developmental trajectories through childhood and adolescence. Some intervention approaches have been demonstrated to be effective in improving core symptoms of ASDs, even if the heterogeneity and developmental nature of the disorder make it implausible that only one specific treatment will be best for all children with ASDs. More randomized control trials (RCTs) on early intervention are needed to identify the most effective strategies and provide the most efficient allocation of resources during the critical early intervention time period. Future research should focus on linking biological phenotypes with specific genotypes, thus establishing a foundation for the development of diagnostic screening tools and individualization of treatments.

Jealousy and emotional responsiveness in young children with ASD

We investigated manifestations of jealousy in preschoolers (n=32) with autism spectrum disorder (ASD) and in a group of typically developing children (n=18) matched on mental age, verbal mental age, nonverbal mental age, and mothers education. Main results revealed explicit indices of jealousy in two thirds of the children with ASD compared with 94.5% in the typical group. In addition, different manifestations of this emotion emerged in the ASD group compared with the matched control group. Regarding mental and affective correlates of jealousy, expressions of jealousy correlated with IQ only for the children in the ASD group, and the ASD group revealed deficient emotional responsiveness (ER) capabilities. Significant correlations emerged between jealousy and ER in both the ASD and control groups. Discussion focuses on implications of these findings for understanding the core emotional deficit in autism.

Treatment of Attention-Deficit/Hyperactivity Disorder (ADHD)

Attention-Deficit/Hyperactivity Disorder (ADHD) is the most common neurobehavioral disorder affecting school-age children. Studies suggest that approximately 8–12% of children (9.2 in males and 3.0 in girls) meet diagnostic criteria for the clinical disorder of ADHD (Faraone, Sergeant, Gillberg, & Biederman, 2003). Approximately 40–70% of those diagnosed with ADHD will have persistent symptoms into adolescence and adulthood with substantial risk of job instability, mood and anxiety disorder, motor vehicle accidents and substance abuse. ADHD is characterized by various symptoms of inattention, and/or impulsivity and is conceptualized as a spectrum, with a range of severity from mild variation of normal behavior to a chronic and severe condition. ADHD affects the individual, the family, and society and can have negative impact on multiple areas of functioning (Wolraich, Hannah, Baumgaertel & Feurer, 1998, American Academy of Pediatrics, 2000). Children with the disorder often suffer from impaired interpersonal relationships with family and peers, academic underachievement and poor self-esteem (Goldman, Genel, & Bezman, & Slanetz, 1998). In addition, children with ADHD commonly exhibit other comorbid developmental and psychiatric disorders that may complicate the intervention plan (Table 6.1; Pliszka, 1998; Spencer, Biederman & Wilens, 1999).