Rutger Jan van der Gaag

Gender and age differences in the core triad of impairments in autism spectrum disorders: a systematic review and meta-analysis.

Autism is an extensively studied disorder in which the gender disparity in prevalence has received much attention. In contrast, only a few studies examine gender differences in symptomatology. This systematic review and meta-analysis of 22 peer reviewed original publications examines gender differences in the core triad of impairments in autism. Gender differences were transformed and concatenated using standardized mean differences, and analyses were stratified in five age categories (toddlerhood, preschool children, childhood, adolescence, young adulthood). Boys showed more repetitive and stereotyped behavior as from the age of six, but not below the age of six. Males and females did not differ in the domain of social behavior and communication. There is an underrepresentation of females with ASD an average to high intelligence. Females could present another autistic phenotype than males. As ASD is now defined according to the male phenotype this could imply that there is an ascertainment bias. More research is needed into the female phenotype of ASD with development of appropriate instruments to detect and ascertain them.

Diagnostic Rules for Children with PDD‐NOS and Multiple Complex Developmental Disorder

This study was designed to examine the classification performance of diagnostic rules for pervasive developmental disorder not otherwise specified (PDD-NOS) and multiple complex developmental disorder (McDD), with clinical diagnosis as the gold standard. McDD is an heuristic concept of a developmental disorder characterised by social impairments, affective dysregulation, and thought disturbance. Detailed information on the symptoms, reliably extracted from the charts of 103 children with PDD-NOS and McDD, 32 with autistic disorder, and 96 with non-PDD disorders, was used to determine the presence of the DSM-IV criteria of autistic disorder and the criteria of McDD. A scoring rule for PDD-NOS based on a short set of seven DSM-IV criteria with a cut-off point of three items and one social interaction item set as mandatory had the best balance between high sensitivity and high specificity. The most effective and simple rule based on McDD criteria had a cut-off of three items, out of six items of anxieties and thought disturbance.

Differentiation between autism and Multiple Complex Developmental Disorder in response to psychosocial stress

Multiple Complex Developmental Disorder (MCDD) represents a distinct group within the autistic spectrum based on symptomatology. Unlike autistic children, part of MCDD children develop schizophrenia in adult life. Despite the differences, patients of both disorders are mainly characterized by abnormal reactions to their social environment. At the biological level, we showed in a previous study that MCDD children have a reduced cortisol response to psychosocial stress. Given the fact that autistic children clinically show more social impairments, it was hypothesized that they may have even further decreased cortisol responses to psychosocial stress than MCDD patients. Therefore, 10 autistic children were compared to 10 MCDD children and 12 healthy control children in their response to a psychosocial stressor, consisting of a public speaking task. In order to test whether any impairments in the biological stress response are specific for psychosocial stress, the autistic children were compared with 11 MCDD children and 15 control children in their response to a physical stressor, consisting of 10 min of bicycle exercise. Heart rate and salivary cortisol levels were used as indicators of response to the stress tests. Autistic children showed a relatively elevated cortisol response to psychosocial stress, in contrast to MCDD children who showed a reduced cortisol response. No differences in heart rate or cortisol responses to the physical stress test were found. The specific difference between autistic and MCDD children in their cortisol response to psychosocial stress indicates that the disturbed reactions to the social environment observed in these disorders may have different biological backgrounds.

The phenotype and neural correlates of language in autism: an integrative review.

Although impaired communication is one of the defining criteria in autism, linguistic functioning is highly variable among people with this disorder. Accumulating evidence shows that language impairments in autism are more extensive than commonly assumed and described by formal diagnostic criteria and are apparent at various levels. Phenotypically, most people with autism have semantic, syntactic and pragmatic deficits, a smaller number are known to have phonological deficits. Neurophysiologically, abnormal processing of low-level linguistic information points to perceptual difficulties. Also, abnormal high-level linguistic processing of the frontal and temporal language association cortices indicates more self-reliant and less connected neural subsystems. Early sensory impairments and subsequent atypical neural connectivity are likely to play a part in abnormal language acquisition in autism. This paper aims to review the available data on the phenotype of language in autism as well as a number of structural, electrophysiological and functional brain-imaging studies to provide a more integrated view of the linguistic phenotype and its underlying neural deficits, and to provide new directions for research and therapeutic and experimental applications.

A Randomized Double-Blind Study of Atomoxetine versus Placebo for Attention-Deficit/Hyperactivity Disorder Symptoms in Children with Autism Spectrum Disorder.

OBJECTIVE The efficacy of atomoxetine as treatment of symptoms of attention-deficit/hyperactivity disorder (ADHD) in patients with autism spectrum disorder (ASD) has not been established. METHOD In this study, 97 patients aged 6 to 17 years with ADHD and ASD were randomly assigned to double-blind treatment with 1.2 mg/kg/day atomoxetine or placebo for 8 weeks. The primary endpoint was the ADHD Rating Scale (ADHD-RS) score; secondary endpoints were the Clinical Global Impression of ADHD-Improvement (CGI-I) and the Conners Teacher Rating Scale-Revised: Short Form (CTRS-R:S) score. RESULTS Baseline mean ADHD-RS scores for atomoxetine versus placebo were 40.7 and 38.6; after 8 weeks, mixed-effect model repeated-measure means were 31.6 (95% confidence interval 29.2-33.9) and 38.3 (36.0-40.6), respectively, with a difference in least square means of -6.7 (-10.0 to -3.4; p < .001). The CTRS-R:S Hyperactivity subscore also improved significantly for atomoxetine compared with placebo, but not the other CTRS-R:S subscores. However, there were not significantly more patients on atomoxetine (20.9%) who improved much, or very much according to the CGI-I, than on placebo (8.7%; p = 0.14). Adverse events (mostly nausea, decrease in appetite, fatigue, and early morning awakening) were reported in 81.3% of atomoxetine patients and 65.3% of placebo patients (p > .1). There were no serious adverse events. CONCLUSIONS Atomoxetine moderately improved ADHD symptoms in patients with ASD and was generally well tolerated. Adverse events in this study were similar to those in other studies with ADHD patients without ASD. Clinical trial registration information-A Randomized Double-Blind Study of Atomoxetine Versus Placebo for ADHD Symptoms in Children with ASD; www.clinicaltrials.gov; NCT00380692.

Basic Abnormalities in Visual Processing Affect Face Processing at an Early Age in Autism Spectrum Disorder

BACKGROUND A detailed visual processing style has been noted in autism spectrum disorder (ASD); this contributes to problems in face processing and has been directly related to abnormal processing of spatial frequencies (SFs). Little is known about the early development of face processing in ASD and the relation with abnormal SF processing. We investigated whether young ASD children show abnormalities in low spatial frequency (LSF, global) and high spatial frequency (HSF, detailed) processing and explored whether these are crucially involved in the early development of face processing. METHODS Three- to 4-year-old children with ASD (n = 22) were compared with developmentally delayed children without ASD (n = 17). Spatial frequency processing was studied by recording visual evoked potentials from visual brain areas while children passively viewed gratings (HSF/LSF). In addition, children watched face stimuli with different expressions, filtered to include only HSF or LSF. RESULTS Enhanced activity in visual brain areas was found in response to HSF versus LSF information in children with ASD, in contrast to control subjects. Furthermore, facial-expression processing was also primarily driven by detail in ASD. CONCLUSIONS Enhanced visual processing of detailed (HSF) information is present early in ASD and occurs for neutral (gratings), as well as for socially relevant stimuli (facial expressions). These data indicate that there is a general abnormality in visual SF processing in early ASD and are in agreement with suggestions that a fast LSF subcortical face processing route might be affected in ASD. This could suggest that abnormal visual processing is causative in the development of social problems in ASD.

Advancing early detection of autism spectrum disorder by applying an integrated two-stage screening approach

BACKGROUND Few field trials exist on the impact of implementing guidelines for the early detection of autism spectrum disorders (ASD). The aims of the present study were to develop and evaluate a clinically relevant integrated early detection programme based on the two-stage screening approach of Filipek et al. (1999), and to expand the evidence base for this approach. METHODS The integrated early detection programme encompassed: 1) training relevant professionals to recognise early signs of autism and to use the Early Screening of Autistic Traits Questionnaire (ESAT; Dietz, Swinkels et al., 2006; Swinkels, van Daalen, van Engeland, & Buitelaar, 2006), 2) using a specific referral protocol, and 3) building a multidisciplinary diagnostic team. The programme was evaluated in a controlled study involving children in two regions (N = 2793, range 0-11 years). The main outcome variables were a difference in mean age at ASD diagnosis and a difference in the proportion of children diagnosed before 36 months. RESULTS ASD was diagnosed 21 months (95% CI 9.6, 32.4) earlier in the experimental region than in the control region during the follow-up period, with the mean age at ASD diagnosis decreasing by 19.5 months (95% CI 10.5, 28.5) from baseline in the experimental region. Children from the experimental region were 9.4 times (95% CI 2.1, 41.3) more likely than children from the control region to be diagnosed before age 36 months after correction for baseline measurements. Most of these early diagnosed children had narrowly defined autism with mental retardation. CONCLUSIONS The integrated early detection programme appears to be clinically relevant and led to the earlier detection of ASD, mainly in children with a low IQ.

Personality Characteristics of Adults With Autism Spectrum Disorders or Attention Deficit Hyperactivity Disorder With and Without Substance Use Disorders

We examined temperament and character profiles of 128 adults with autism spectrum disorder (ASD) or attention deficit and hyperactivity disorder (ADHD). Participants completed the abbreviated Temperament and Character Inventory. The ASD and ADHD groups showed distinct temperament profiles (ADHD: high novelty seeking, ASD: low reward dependence, high harm avoidance) and low character scores in both groups. We then stratified ASD and ADHD into current substance use disorder (SUD+), former (SUDˆ), or no history of Substance Use Disorder (SUD−). Novelty seeking and reward dependence were only significantly lower for ASD/SUD−, but normal for ASD/SUDˆ and ASD/SUD+ subgroups. Persistence scores were highest in both SUDˆ subgroups. We concluded that temperament profiles of ASD and ADHD patients differ significantly, and are similar to profiles reported in earlier studies, but appear to depend on the SUD status. Surprisingly, normal social orientation is found in ASD patients with former or current SUD. High persistence scores characterize patients who overcome SUD.

Treatment seeking adults with autism or ADHD and co-morbid Substance Use Disorder: Prevalence, risk factors and functional disability

BACKGROUND Little is known about Autism Spectrum Disorder (ASD) in adults, especially not about ASD with co-morbid Substance Use Disorder (SUD). We wanted to examine how adults with ASD compare to adults with ADHD on prevalence and risk factors for co-morbid SUD, and on disability levels associated with SUD. METHODS We stratified 123 treatment seeking adults with ASD (n=70) or ADHD (n=53), into current, former and no history of SUD (SUD+, SUD(wedge), and SUD-), and conducted interviews to explore associated risk factors and current levels of disability. RESULTS Prevalence of co-morbid SUD was higher in ADHD than in ASD in our sample (58% versus 30%, p=0.001). There was no statistically significant difference between ASD and ADHD in risk factors or disability scores. Patients with lifetime SUD started regular smoking earlier in life (OR=5.69, C(95%) 2.3-13.8), reported more adverse family events (OR=2.68; CI(95%) 1.2-6.1), and had more parental SUD (OR=5.36; CI(95%) 1.0-14.5). Disability scores were significantly lower in SUD- and SUD(wedge) groups compared to the SUD+ group. DISCUSSION These findings suggest that ASD and ADHD share similar risk factors for SUD. High disability in ASD and ADHD with SUD may normalize after prolonged abstinence. Early onset of SUD was not associated with more severe disability scores than later onset. Results suggest that a subgroup of patients with former SUD may have a higher level of functioning before the onset of SUD in comparison to those without lifetime SUD.

How useful is the Social Communication Questionnaire in toddlers at risk of autism spectrum disorder

BACKGROUND The Social Communication Questionnaire (SCQ) is a screening instrument with established validity against the Autism Diagnostic Interview-Revised (ADI-R) in children aged 4 years and older. Indices of diagnostic accuracy have been shown to be strong in school-aged samples; however, relatively little is known about the performance of the SCQ in toddlers at risk of autism spectrum disorder (ASD). METHODS This study replicates and extends previous research by Corsello et al. (2007) in a comparatively large (N = 208), substantially younger (20-40 months) sample of children at high risk of ASD. The usefulness of the SCQ as a second-level screening instrument with different cut-off scores was evaluated in relation to IQ, age, and type of ASD diagnosis. The use of the SCQ as compared to the ADI-R was evaluated against clinical diagnosis, both alone and in combination with the ADOS. RESULTS The SCQ with different cut-offs consistently showed an unsatisfactory balance between sensitivity and specificity in screening for ASD in high-risk toddlers, with only a few exceptions for specific age, IQ, or diagnostic groups. Even though the SCQ and ADI-R were highly correlated, diagnostic agreement with the best evidence clinical diagnosis was poor for both measures. The ADOS used alone consistently had the highest predictive value. For autism versus not-autism, the combined SCQ and ADOS performed as well as the ADOS alone and notably better than the combination ADI-R and ADOS. CONCLUSIONS The SCQ is likely to result in a number of false-positive findings, particularly in children with autism symptomatology, and the balance between sensitivity and specificity is poor. The ADOS should be considered the most valid and reliable diagnostic instrument in these very young at-risk children.