Convergence of genes and cellular pathways dysregulated in autism spectrum disorders.

Rare copy-number variation (CNV) is an important source of risk for autism spectrum disorders (ASDs). We analyzed 2,446 ASD-affected families and confirmed an excess of genic deletions and duplications in affected versus control groups (1.41-fold, p = 1.0 × 10(-5)) and an increase in affected subjects carrying exonic pathogenic CNVs overlapping known loci associated with dominant or X-linked ASD and intellectual disability (odds ratio = 12.62, p = 2.7 × 10(-15), ∼3% of ASD subjects). Pathogenic CNVs, often showing variable expressivity, included rare de novo and inherited events at 36 loci, implicating ASD-associated genes (CHD2, HDAC4, and GDI1) previously linked to other neurodevelopmental disorders, as well as other genes such as SETD5, MIR137, and HDAC9. Consistent with hypothesized gender-specific modulators, females with ASD were more likely to have highly penetrant CNVs (p = 0.017) and were also overrepresented among subjects with fragile X syndrome protein targets (p = 0.02). Genes affected by de novo CNVs and/or loss-of-function single-nucleotide variants converged on networks related to neuronal signaling and development, synapse function, and chromatin regulation.

Individual prediction of long-term outcome in adolescents at ultra-high risk for psychosis: Applying machine learning techniques to brain imaging data.

An important focus of studies of individuals at ultra-high risk (UHR) for psychosis has been to identify biomarkers to predict which individuals will transition to psychosis. However, the majority of individuals will prove to be resilient and go on to experience remission of their symptoms and function well. The aim of this study was to investigate the possibility of using structural MRI measures collected in UHR adolescents at baseline to quantitatively predict their long-term clinical outcome and level of functioning. We included 64 UHR individuals and 62 typically developing adolescents (12-18 years old at recruitment). At six-year follow-up, we determined resilience for 43 UHR individuals. Support Vector Regression analyses were performed to predict long-term functional and clinical outcome from baseline MRI measures on a continuous scale, instead of the more typical binary classification. This led to predictive correlations of baseline MR measures with level of functioning, and negative and disorganization symptoms. The highest correlation (r = 0.42) was found between baseline subcortical volumes and long-term level of functioning. In conclusion, our results show that structural MRI data can be used to quantitatively predict long-term functional and clinical outcome in UHR individuals with medium effect size, suggesting that there may be scope for predicting outcome at the individual level. Moreover, we recommend classifying individual outcome on a continuous scale, enabling the assessment of different functional and clinical scales separately without the need to set a threshold. Hum Brain Mapp 38:704-714, 2017. © 2016 Wiley Periodicals, Inc.

Differences in ADHD medication usage patterns in children and adolescents from different cultural backgrounds in the Netherlands.

PURPOSE: Differences in incidence and prevalence of ADHD medication use between ethnic groups have been reported. Goal of this study was to determine whether there are also differences in usage patterns of ADHD medication among native Dutch children and adolescents and those with a Moroccan, Turkish and Surinam cultural background in the Netherlands between 1999 and 2010. METHODS: In a cohort of ADHD patients <19 years (N = 817) incident use and discontinuation of ADHD medication were measured for ethnicity and adjusted for age, gender and socio-economic status. RESULTS: A significant higher proportion of ADHD-diagnosed patients from Moroccan (32 %) and Turkish (42 %) cultural background never used ADHD medication compared to Dutch natives (21 %). One-fifth of native Dutch and Turkish patients already used ADHD medication before the ADHD diagnosis date. Discontinuation of ADHD medication within 5 years was significantly higher in Moroccan [HR 2.4 (95 % CI 1.8-3.1)] and Turkish [HR 1.7 (95 % CI 1.1-2.6)] patients. A sensitivity analysis with a zip code-matched comparison between Dutch natives and non-natives showed similar results, suggesting this effect is probably not explained by socio-economic status (SES). CONCLUSION: Differences are found in prescribing and use of ADHD medication between patients with a different cultural background. Native Dutch and Turkish patients start more frequently with ADHD medication before the ADHD diagnose date, which can be an indication of differences in either referral patterns and/or access to care. A higher percentage of patients with a Moroccan and Turkish cultural background never start using ADHD medication at all and discontinuation rate is higher compared to Dutch natives and Surinamese.

Quality of life: a case-controlled long-term follow-up study, comparing young high-functioning adults with autism spectrum disorders with adults with other psychiatric disorders diagnosed in childhood.

BACKGROUND: Long term outcome in childhood autism spectrum disorders (ASD) was evaluated by studying quality of life (QoL) in young adulthood in comparison to the outcome of other child psychiatric disorders. METHODS: In this follow-up study, objective and subjective QoL of 169 high-functioning (IQ>70) adults with ASD (19 to 30 years) was contrasted with QoL data of age matched adults diagnosed with attention deficit/hyperactivity disorder (N=85), disruptive behaviour disorders (N=83), and affective disorders (N=85) during childhood. The mean follow-up period of the ASD patients was 13.9 years. Objective QoL included marital status, living arrangements, level of education, employment, and usage of mental health care. Subjective QoL included satisfaction concerning living arrangements, work or education, physical condition, partner relationship, social relationships, state of mind, and future perspective. RESULTS: QoL was more compromised in adults diagnosed with ASD in childhood than in adults with other psychiatric disorders in childhood. A relatively large proportion of the adults with ASD were single, few lived with a partner or a family and many of them were institutionalized. Adults with ASD had lower educational levels, relatively few had paid employment and many were social security recipients, as compared to the other psychiatric patients. In case the adults with ASD used medication, 47% used anti-psychotics. Regarding the subjective QoL, the adults with ASD were less satisfied about their work or education, partner relationship, and future perspective than the other groups. Even when highly educated adults with ASD were compared to highly educated adults diagnosed with other childhood disorders, the QoL appeared to be more disadvantageous in adults with ASD. CONCLUSION: Many studies have shown that QoL is threatened in psychiatric patients, but findings of this study indicate that young high-functioning adults diagnosed with ASD in childhood are at relatively high risk for poor QoL compared to other childhood psychiatric disorders.

Association between ADHD drug use and injuries among children and adolescents.

To study the association between attention deficit hyperactivity disorder (ADHD) drug use and the incidence of hospitalization due to injuries. A random sample of 150,000 persons (0-18 years) was obtained from the Dutch PHARMO record linkage system. An ADHD medication cohort as well as an up to six age/sex/index date sampled control cohort with no history of ADHD drug use was formed. Differences in incidence of hospitalization due to injuries were stratified for age and sex and compared prior, during and after exposure on ADHD drugs. The overall incidence of hospital admissions for injuries was two times higher in the ADHD medication cohort [incidence rate ratios (IRR) 2.2 (95 % CI 1.6-2.9)]. The incidence rate for injuries during exposure to ADHD drugs was lower in the exposed period compared to the period prior to ADHD drug use, although the difference was not statistically significant [IRR 0.68 (95 % CI 0.29-1.60)]. The relative risk for injuries was almost five times higher in the ADHD medication cohort among those who concomitantly used other psychotropics [IRR 4.8 (95 % CI 1.4-16.9)]. Risk for injuries was highest in 12-18 years olds. Children and adolescents using ADHD medication showed a twofold risk for hospital admissions for injuries. ADHD drug use might diminish the increased injury risk, but still overall risk is higher than in age/sex sampled children and adolescents without treatment with ADHD drugs. Use of ADHD and concomitant psychotropics increases the risk for injuries compared to only ADHD drug use.

Development of a Video-feedback Intervention to promote Positive Parenting for Children with Autism (VIPP-AUTI).

In this paper we describe the development and content of Video-feedback Intervention to promote Positive Parenting for Children with Autism (VIPP-AUTI). VIPP-AUTI is an adapted version of the evidence-based intervention VIPP. The lack of social responsiveness in children with autism often lowers the quality of the parent-child interaction. A wide range of early interventions exist to cope with the disorder. The majority of early interventions for children with autism focus on their deficits of (social) skills, but the number of evidence-based interventions to improve early parent-child interaction patterns is limited. The aim of VIPP-AUTI is to enhance parental sensitivity to children's autistic characteristics, in order to improve child developmental outcome by increased parental support.

Parental reaction to early diagnosis of their children's autism spectrum disorder: an exploratory study.

This study explores parental reactions subsequent to receiving their child's autism spectrum disorder (ASD)-diagnosis. Seventy seven parents of recently diagnosed children participated in the Reaction to Diagnosis Interview. Within this group, associations between parental reaction to diagnosis, parental and child characteristics and prediagnostic circumstances were analysed. In a sub-sample, the stability of reaction to diagnosis was examined. The majority of parents were classified as 'resolved' regarding their child's diagnosis. Conversely, parents of children with more severe ASD symptoms or non-Dutch parents were more likely to be classified as 'unresolved'. Sub-sample analysis revealed stability of reaction to ASD-diagnosis. The majority of parents adapted well to the circumstances and the care for their child. Autism severity and parental nationality were significant factors affecting parental reactions. Thus, early identification of parental reaction to children's ASD-diagnosis may aid in providing more tailored parental support programs.

Impaired response inhibition in autism spectrum disorders, a marker of vulnerability to schizophrenia spectrum disorders?

In this study, we addressed the relation between specific deficits in cognitive control and schizotypal symptomatology in adolescents with autism spectrum disorders (ASD) diagnosed in childhood. We aimed to identify cognitive control deficits as markers of vulnerability to the development of schizophrenia spectrum pathology in ASD. Symptoms of autism and the risk for schizotypal symptomatology were assessed in 29 high-functioning adolescents with ASD, and compared with 40 typically developing adolescents. Cognitive control (response inhibition, mental flexibility, visuo-motor control, interference control, and perseveration) was evaluated for specific association with schizotypal symptomatology. Impaired response inhibition appeared to be strongly and specifically associated with schizotypal symptomatology in adolescents with ASD, especially those with positive and disorganized symptoms. Response inhibition problems could indicate vulnerability to the development of schizotypal symptomatology in ASD.

Development of schizotypal symptoms following psychiatric disorders in childhood or adolescence.

It was examined how juvenile psychiatric disorders and adult schizotypal symptoms are associated. 731 patients of the Department of Child and Adolescent Psychiatry of the University Medical Centre Utrecht, the Netherlands, with mean age of 12.1 years (SD = 4.0) were reassessed at the mean age of 27.9 years (SD = 5.7) for adult schizotypal symptoms using the Schizotypal Personality Questionnaire-Revised (Vollema, Schizophr Bull 26(3):565-575, 2000). Differences between 13 juvenile DSM categories and normal controls (n = 80) on adult schizotypal total and factor scores were analyzed, using (M)ANCOVA. Pervasive developmental disorders (PDD), attention deficit hyperactivity disorders (ADHD), deferred diagnosis, sexual and gender identity disorders and depressive disorders had higher SPQ total scores when compared to normal controls (p < 0.001). Higher levels of disorganized schizotypal symptoms were found for PDD, ADHD, and deferred diagnosis (p < 0.001). The same diagnostic groups showed higher level of negative schizotypal symptoms, which was likewise true for sexual and gender identity disorders, depressive disorders, disruptive disorders, and the category of 'Other conditions that may be a focus of clinical attention' (p < 0.001). No differences with normal controls were found for adult positive schizotypal symptoms (p < 0.110). The current findings are suggestive of the idea that psychiatric disorders in childhood or adolescence are a more general expression of a liability to schizophrenia spectrum pathology in future life. In addition, specific patterns of adult schizotypal symptomatology are associated with different types of juvenile psychiatric disorder.

No evidence that common genetic risk variation is shared between schizophrenia and autism.

The similarity between aspects of the clinical presentation of schizophrenia and autism spectrum disorders (ASD) suggests that elements of the biological etiology may also be shared between these two disorders. Recently, an increasing number of rare, mostly structural genetic variants are reported to increase the risk of both schizophrenia and ASD. We hypothesized that given this evidence for a shared genetic background based on rare genetic variants, common risk alleles may also be shared between ASD and schizophrenia. To test this hypothesis, the polygenic score, which summarizes the collective effect of a large number of common risk alleles, was used. We examined whether the polygenic score derived from a schizophrenia case-control dataset, previously reported by Purcell et al., was able to differentiate ASD cases from controls. The results demonstrate that the schizophrenia-derived polygenic score is not different between ASD cases and controls, indicating that there is no important sharing of common risk alleles between the two neuropsychiatric disorders. Possibly, common risk alleles are less important in ASD in comparison to their more prominent role in schizophrenia and bipolar disorders. These findings provide important novel insights into shared and distinct elements of the genetic architecture of autism and schizophrenia.

Decreased frontostriatal microstructural organization in attention deficit/hyperactivity disorder.

Frontostriatal brain areas have been implicated in the neurobiology of attention deficit/hyperactivity disorder (ADHD), but little work has directly addressed the white matter connections between these regions. The present study investigates the microstructural organization and myelination of frontostriatal white matter in children with ADHD and controls. Diffusion tensor imaging and magnetization transfer imaging scans were acquired in 30 children with ADHD and 34 controls. A study specific volume of interest (VOI) of frontostriatal white matter was created using a tractography based statistical group map. Fractional anisotropy (FA, indexing microstructural organization) and magnetization transfer ratio (MTR, indexing macromolecular content, myelin in particular) were computed for the frontostriatal VOI and for total cerebral white matter. Exploratory analyses were conducted investigating the effect of stimulant use on these measures. Frontostriatal FA but not MTR was decreased in ADHD compared with controls. There were no differences in FA or MTR for total cerebral white matter. Frontostriatal FA correlated negatively with teacher-rated attention problems in controls but not children with ADHD. The duration of stimulant use did not affect the main results. Changes in frontostriatal connectivity in ADHD appear to be related to changes in microstructural organization rather than myelination per se. A correlation with attention problems for controls suggests that frontostriatal organization is relevant to ADHD-related behaviors.

Quality of life and academic functioning 6 years after paediatric referral for chronic pain.

AIM: To assess health-related quality of life (HR-QoL) and academic functioning in adolescents and young adults 6 years after paediatric referral for chronic pain. METHODS: In 99 children and adolescents with chronic pain (aged 8-17) referred to a paediatric outpatient clinic, pain and psychiatric disorders were assessed between 2000 and 2002. Participants were reassessed after minimal 5 years (aged 13-24). HR-QoL [Medical Outcomes Study 36-item Short-Form (SF-36)] was compared with Dutch population norms. Academic functioning (structured questionnaire) was compared with baseline. RESULTS: Participant's ratings in most HR-QoL dimensions did not differ from population norms. Outcome was significantly decreased in Bodily Pain (p = 0.001 males, p < 0.000 females) and female General Health (p = 0.001). Poor general health perceptions (p = 0.002), poor global general health (p = 0.003) and a high somatic symptom level (p = 0.004) at baseline predicted poor HR-QoL outcome. School/work attendance was significantly better than at baseline (p = 0.002). CONCLUSION: Six years after paediatric referral for chronic pain, HR-QoL was mostly comparable to that of peers, and academic functioning improved. Self-evaluated global health at referral may be an important predictor of HR-QoL outcome of children with chronic pain, rather than psychiatric comorbidity.

Functional connectivity between cognitive control regions is sensitive to familial risk for ADHD.

Familial risk for attention-deficit hyperactivity disorder (ADHD) has been associated with changes in brain activity related to cognitive control. However, it is not clear whether changes in activation are the primary deficit or whether they are related to impaired communication between regions involved in this ability. We investigated whether (1) functional connectivity between regions involved in cognitive control was affected by familial risk and (2) changes were specific to these regions. Correlational seed analyses were used to investigate temporal covariance between cognitive control and motor regions in two independent samples of typically developing controls, subjects with ADHD and their unaffected siblings. In both samples, correlation coefficients between cognitive control regions were greater for typically developing controls than for subjects with ADHD, with intermediate values for unaffected siblings. Within the motor network, unaffected siblings showed correlations similar to typically developing children. There were no differences in activity between the brain regions involved. These data show that functional connectivity between cognitive control regions is sensitive to familial risk for ADHD. Results suggest that changes in connectivity associated with cognitive control may be suitable as an intermediate phenotype for future studies.

Reduced prepulse inhibition in adolescents at risk for psychosis: a 2-year follow-up study.

BACKGROUND: Reduced prepulse inhibition (PPI) of the auditory startle reflex is a hallmark feature of attention-processing deficits in patients with schizophrenia and other psychotic disorders. Recent evidence suggests that these deficits may also be present before the onset of psychosis in individuals at ultra-high risk (UHR) and become progressively worse as psychosis develops. We conducted a longitudinal follow-up study to observe the development of PPI over time in UHR adolescents and healthy controls. METHODS: Two-year follow-up data of PPI measures were compared between UHR adolescents and a matched control group of typically developing individuals. RESULTS: We included 42 UHR adolescents and 32 matched controls in our study. Compared with controls, UHR individuals showed reduced PPI at both assessments. Clinical improvement in UHR individuals was associated with an increase in PPI parameters. LIMITATIONS: A developmental increase in startle magnitude partially confined the interpretation of the association between clinical status and PPI. Furthermore, post hoc analyses for UHR individuals who became psychotic between assessments had limited power owing to a low transition rate (14%). CONCLUSION: Deficits in PPI are present before the onset of psychosis and represent a stable vulnerability marker over time in UHR individuals. The magnitude of this marker may partially depend on the severity of clinical symptoms.

Affective dysfunctions in adolescents at risk for psychosis: emotion awareness and social functioning.

Studies of individuals at ultra high risk (UHR) for psychosis have revealed deviations in cognitive and neural development before the onset of psychosis. As affective impairments are among the core dysfunctions in psychotic disorders such as schizophrenia, this study assessed emotion processing and the relationship with social competence in adolescents at risk for psychosis. Thirty-four adolescents at UHR for psychosis and twenty-three non-clinical controls completed the Bermond-Vorst Alexithymia Questionnaire, a measure of emotion awareness. Social inadequacy was measured using the Dutch Personality Questionnaire. Schizophrenia spectrum psychopathology was assessed using self-report and clinical instruments. The Wechsler Adult Intelligence Scale (WAIS) was used to evaluate intellectual functioning. UHR adolescents showed difficulties in identifying and verbalizing their own emotions, independent of intelligence scores. Emotion awareness problems were related to social inadequacy and schizotypal traits in the high risk group. These findings suggest that UHR adolescents may have reduced emotion awareness, independent of intellectual functioning. The relationship with social inadequate behavior fits with the idea that emotion awareness is a prerequisite for the regulation of emotions in social contexts. In the search for early vulnerability markers of risk for psychosis, studying emotion processing besides cognitive abilities might increase our understanding of 'at risk' developmental pathways.

Psychiatric disorders in children and adolescents presenting with unexplained chronic pain: what is the prevalence and clinical relevancy?

The prevalence of psychiatric disorders among children with unexplained chronic pain (UCP) is high in unselected populations and pain clinics, yet the clinical relevance of these disorders in children referred for unexplained pain is not known. This study assessed the prevalence of clinically relevant psychiatric disorders and their predictors in children referred to a children's hospital for UCP. Psychiatry morbidity was assessed in 134 children, aged 8-17 years, using the Diagnostic Interview Schedule for Children-parent version (DISC-P) and the Semi-structured Clinical Interview for Children and Adolescents (SCICA). Clinical relevance was determined using a maladjustment criterion of 61 or lower on the Children's Global Assessment Scale (CGAS). Pain parameters were measured with standardized questionnaires. Results were analysed by logistic regression. According to the DISC-P, 21% of the children had clinically relevant psychiatric disorders, predominantly anxiety disorders (18%). According to the SCICA, 28% of the children had clinically relevant psychiatric disorders, consisting of anxiety, affective, and disruptive disorders (12, 19, and 9%, respectively). Headache (compared to musculoskeletal pain) was an independent clinical predictor of psychiatric morbidity (OR = 3.10; 95% CI 1.07-8.92, p = 0.04/adjusted OR 2.99; 95% CI 1.02-8.74, p = 0.04). In conclusion, clinically relevant psychiatric disorders are common among children and adolescents referred for UCP. Adding a child psychiatrist assessment, treatable affective and disruptive disorders become identifiable. Children with an additional risk are those presenting with headache.

Cross-sectional study into the costs and impact on family functioning of 4-year-old children with aggressive behavior.

Early-onset aggressive behavior is known for its negative developmental consequences, and the associated high costs for families, the health care system and wider society. Although the origins of aggressive behavior are to be found in early childhood, the costs incurred by aggressive behavior of young children have not been studied extensively. The present study aimed to investigate whether preschool children with a high level of aggressive behavior already differ in the generated amount of costs and impact on family functioning from children with lower levels of aggressive behavior. A population-based sample of 317 preschool children was divided into four groups with different levels of aggression (moderate, borderline, clinical). Parents filled out questionnaires to assess service use (lifetime and past 3 months) and impact on family functioning. Over the past 3 months as well as over the first 4 years of life, children with a clinical level of aggression were more costly than children with a low level of aggression (mean total costs over the past 3 months: low € = 167,05 versus clinical € = 1034,83 and mean lifetime costs: low € = 817,37 versus clinical € = 1433,04), due to higher costs of services used by the child. In addition, families of children with a borderline or clinical level of aggressive behavior reported more impairment in their daily functioning than families of children with lower levels of aggression. The findings demonstrate that a high level of aggressive behavior results in high costs and impaired family functioning in the preschool years already.

Children's aggressive responses to neutral peer behavior: a form of unprovoked reactive aggression.

Previous studies that operationalized reactive aggression using behavioral observations in general populations have not taken into account the type of stimulus that elicits reactive aggression. In the present study we define a specific form of reactive aggression, i.e., reactive aggression in response to neutral behavior of a peer, which we will call unprovoked reactive aggression. We were specifically interested in children with severe aggressive behavior problems, since they may respond with reactive aggression even though the opponent did not clearly provoke them, but instead showed neutral behavior. Children with a disruptive behavior disorder (DBD) and normal control (NC) children participated in separate play sessions in which they played with a normal peer (NP). Children with DBD showed more unprovoked reactive aggression than NC children, during a cooperative game. Moreover, for children with DBD, unprovoked reactive aggressive behavior in this game correlated with parent-rated reactive aggression. Results of this study suggest that an unprovoked reactive form of aggression can be identified in children with DBD.

A co-segregating microduplication of chromosome 15q11.2 pinpoints two risk genes for autism spectrum disorder.

High resolution genomic copy-number analysis has shown that inherited and de novo copy-number variations contribute significantly to autism pathology, and that identification of small chromosomal aberrations related to autism will expedite the discovery of risk genes involved. Here, we report a microduplication of chromosome 15q11.2, spanning only four genes, co-segregating with autism in a Dutch pedigree, identified by SNP microarray analysis, and independently confirmed by FISH and MLPA analysis. Quantitative RT-PCR analysis revealed over 70% increase in peripheral blood mRNA levels for the four genes present in the duplicated region in patients, and RNA in situ hybridization on mouse embryonic and adult brain sections revealed that two of the four genes, CYFIP1 and NIPA1, were highly expressed in the developing mouse brain. These findings point towards a contribution of microduplications at chromosome 15q11.2 to autism, and highlight CYFIP1 and NIPA1 as autism risk genes functioning in axonogenesis and synaptogenesis. Thereby, these findings further implicate defects in dosage-sensitive molecular control of neuronal connectivity in autism. However, the prevalence of this microduplication in patient samples was statistically not significantly different from control samples (0.94% in patients vs. 0.42% controls, P = 0.247), which suggests that our findings should be interpreted with caution and indicates the need for studies that include large numbers of control subjects to ascertain the impact of these changes on a population scale.

A neural substrate for atypical low-level visual processing in autism spectrum disorder.

An important characteristic of autism spectrum disorder (ASD) is increased visual detail perception. Yet, there is no standing neurobiological explanation for this aspect of the disorder. We show evidence from EEG data, from 31 control subjects (three females) and 13 subjects (two females) aged 16-28 years, for a specific impairment in object boundary detection in ASD, which is present as early as 120 ms after stimulus presentation. In line with a neural network model explicating the role of feedforward, horizontal and recurrent processing in visual perception, we can attribute this deficit to a dysfunction of horizontal connections within early visual areas. Interestingly, ASD subjects showed an increase in subsequent activity at lateral occipital sites (225 ms), which might reflect a compensational mechanism. In contrast, recurrent processing between higher and lower visual areas (around 260 ms), associated with the segregation between figure and background, was normal. Our results show specific neural abnormalities in ASD related to low-level visual processing. In addition, given the reconciliation between our findings and previous neuropathology and neurochemistry research, we suggest that atypical horizontal interactions might reflect a more general neural abnormality in this disorder.