Parent-child interaction during the first year of life in infants at elevated likelihood of autism spectrum disorder.

Autism spectrum disorder (ASD) likely emerges from a complex interaction between pre-existing neurodevelopmental vulnerabilities and the environment. The interaction with parents forms a key aspect of an infant's social environment, but few prospective studies of infants at elevated likelihood (EL) for ASD (who have an older sibling with ASD) have examined parent-child interactions in the first year of life. As part of a European multisite network, parent-child dyads of free play were observed at 5 months (62 EL infants, 47 infants at typical likelihood (TL)) and 10 months (101 EL siblings, 77 TL siblings). The newly-developed Parent-Infant/Toddler Coding of Interaction (PInTCI) scheme was used, focusing on global characteristics of infant and parent behaviors. Coders were blind to participant information. Linear mixed model analyses showed no significant group differences in infant or parent behaviors at 5 or 10 months of age (all ps≥0.09, d≤0.36), controlling for infant's sex and age, and parental educational level. However, without adjustments, EL infants showed fewer and less clear initiations at 10 months than TL infants (p = 0.02, d = 0.44), but statistical significance was lost after controlling for parental education (p = 0.09, d = 0.36), which tended to be lower in the EL group. Consistent with previous literature focusing on parent-infant dyads, our findings suggest that differences between EL and TL dyads may only be subtle during the first year of life. We discuss possible explanations and implications for future developmental studies.

Role of conduct problems in the relation between Attention-Deficit Hyperactivity disorder, substance use, and gaming.

Known comorbidities for Attention-Deficit Hyperactivity Disorder (ADHD) include conduct problems, substance use disorder and gaming. Comorbidity with conduct problems may increase the risk for substance use disorder and gaming in individuals with ADHD. The aim of the study was to build a causal model of the relationships between ADHD and comorbid conduct problems, and alcohol, nicotine, and other substance use, and gaming habits, while accounting for age and sex. We used a state-of-the-art causal discovery algorithm to analyze a case-only sample of 362 ADHD-diagnosed individuals in the ages 12-24 years. We found that conduct problem severity mediates between ADHD severity and nicotine use, but not with more severe alcohol or substance use. More severe ADHD-inattentive symptoms lead to more severe gaming habits. Furthermore, our model suggests that ADHD severity has no influence on severity of alcohol or other drug use. Our findings suggest that ADHD severity is a risk factor for nicotine use, and that this effect is fully mediated by conduct problem severity. Finally, ADHD-inattentive severity was a risk factor for gaming, suggesting that gaming dependence has a different causal pathway than substance dependence and should be treated differently. By identifying these intervention points, our model can aid both researchers and clinicians.

The mediating role of joint attention in the relationship between motor skills and receptive and expressive language in siblings at risk for autism spectrum disorder.

Language problems are highly prevalent in younger siblings of children with autism spectrum disorder (HR-sibs), yet little is known about early predictors. There is growing evidence that motor and language development are linked and this connection might be mediated by joint attention. Developmental changes in motor abilities change how children interact with objects and people (e.g., by showing), which may influence language development. This association has however not yet been studied in HR-sibs. The interrelationship between motor, joint attention and language skills was explored in younger siblings of typically developing children (LR-sibs, N = 31) and HR-sibs (N = 32). In both groups, motor skills (composite of fine and gross motor skills) at 10 months influenced receptive and expressive language at 36 months directly and indirectly through joint attention at 14 months. Group status moderated this direct and indirect effect with mainly significant effects in HR-sibs. This indicates that lower motor skills can have cascading effects on joint attention and language in HR-sibs. Consequently, assessment of early motor skills in HR-sibs might hold promise for early identification of motor difficulties but can also be indicative of language difficulties later in life, especially when difficulties with joint attention are also present.

Eurosibs: Towards robust measurement of infant neurocognitive predictors of autism across Europe.

Autism Spectrum Disorder (ASD) is a neurodevelopmental disorder that affects social communication skills and flexible behaviour. Developing new treatment approaches for ASD requires early identification of the factors that influence later behavioural outcomes. One fruitful research paradigm has been the prospective study of infants with a first degree relative with ASD, who have around a 20% likelihood of developing ASD themselves. Early findings have identified a range of candidate neurocognitive markers for later ASD such as delayed attention shifting or neural responses to faces, but given the early stage of the field most sample sizes are small and replication attempts remain rare. The Eurosibs consortium is a European multisite neurocognitive study of infants with an older sibling with ASD conducted across nine sites in five European countries. In this manuscript, we describe the selection and standardization of our common neurocognitive testing protocol. We report data quality assessments across sites, showing that neurocognitive measures hold great promise for cross-site consistency in diverse populations. We discuss our approach to ensuring robust data analysis pipelines and boosting future reproducibility. Finally, we summarise challenges and opportunities for future multi-site research efforts.

Evaluating Sex and Age Differences in ADI-R and ADOS Scores in a Large European Multi-site Sample of Individuals with Autism Spectrum Disorder.

Research on sex-related differences in Autism Spectrum Disorder (ASD) has been impeded by small samples. We pooled 28 datasets from 18 sites across nine European countries to examine sex differences in the ASD phenotype on the ADI-R (376 females, 1763 males) and ADOS (233 females, 1187 males). On the ADI-R, early childhood restricted and repetitive behaviours were lower in females than males, alongside comparable levels of social interaction and communication difficulties in females and males. Current ADI-R and ADOS scores showed no sex differences for ASD severity. There were lower socio-communicative symptoms in older compared to younger individuals. This large European ASD sample adds to the literature on sex and age variations of ASD symptomatology.

Default mode network abnormalities during state switching in attention deficit hyperactivity disorder.

BACKGROUND: Individuals with attention deficit hyperactivity disorder (ADHD) display excess levels of default mode network (DMN) activity during goal-directed tasks, which are associated with attentional disturbances and performance decrements. One hypothesis is that this is due to attenuated down-regulation of this network during rest-to-task switching. A second related hypothesis is that it may be associated with right anterior insula (rAI) dysfunction - a region thought to control the actual state-switching process. METHOD: These hypotheses were tested in the current fMRI study in which 19 adults with ADHD and 21 typically developing controls undertook a novel state-to-state switching paradigm. Advance cues signalled upcoming switches between rest and task periods and switch-related anticipatory modulation of DMN and rAI was measured. To examine whether rest-to-task switching impairments may be a specific example of a more general state regulation deficit, activity upon task-to-rest cues was also analysed. RESULTS: Against our hypotheses, we found that the process of down-regulating the DMN when preparing to switch from rest to task was unimpaired in ADHD and that there was no switch-specific deficit in rAI modulation. However, individuals with ADHD showed difficulties up-regulating the DMN when switching from task to rest. CONCLUSIONS: Rest-to-task DMN attenuation seems to be intact in adults with ADHD and thus appears unrelated to excess DMN activity observed during tasks. Instead, individuals with ADHD exhibit attenuated up-regulation of the DMN, hence suggesting disturbed re-initiation of a rest state.

How can clinicians detect and treat autism early? Methodological trends of technology use in research.

UNLABELLED: We reviewed original research papers that used quantifiable technology to detect early autism spectrum disorder (ASD) and identified 376 studies from 34 countries from 1965 to 2013. Publications have increased significantly since 2000, with most coming from the USA. Electroencephalogram, magnetic resonance imaging and eye tracking were the most frequently used technologies. CONCLUSION: The use of quantifiable technology to detect early ASD has increased in recent decades, but has had limited impact on early detection and treatment. Further scientific developments are anticipated, and we hope that they will increasingly be used in clinical practice for early ASD screening, diagnosis and intervention.

Impulsive choice predicts short-term relapse in substance-dependent individuals attending an in-patient detoxification programme.

BACKGROUND: Impulsivity is a hallmark characteristic of substance use disorders. Recently, studies have begun to explore whether increased impulsivity in substance-dependent individuals (SDIs) is associated with a greater propensity to relapse following treatment. Despite growing recognition of its multidimensional nature, however, most studies have treated impulsivity unilaterally. Accordingly, it remains unclear whether certain facets of impulsivity are more relevant to relapse than others. The aim of the current study was to examine the relationship between multiple facets of impulsivity and short-term relapse in SDIs. As a secondary aim, we explored the role of treatment retention in this relationship. METHOD: A personality-based impulsivity questionnaire (UPPS) and three neurocognitive tasks of impulsivity [stop-signal task (SST), delay discounting task (DDT) and Iowa gambling task (IGT)] were administered in a heterogeneous sample of 70 SDIs shortly following their entry in an in-patient detoxification programme. Mediation analyses were performed to explore whether the effects of impulsivity on relapse were mediated by treatment retention. RESULTS: Performance on two neurocognitive indices of impulsive choice (i.e. delay discounting and impulsive decision-making) significantly predicted short-term relapse. The effects of delay discounting and impulsive decision-making on relapse propensity were mediated by treatment retention. CONCLUSIONS: Neurocognitive indices of impulsivity may be more sensitive to the prediction of relapse than trait-based self-report questionnaires. Post-treatment relapse in SDIs may be reduced by targeting the processes involved in impulsive choice and by improving treatment retention in SDIs with inflated impulsivity.

Genetic analysis of reaction time variability: room for improvement?

BACKGROUND: Increased reaction time variability (RTV) on cognitive tasks requiring a speeded response is characteristic of several psychiatric disorders. In attention deficit hyperactivity disorder (ADHD), the association with RTV is strong phenotypically and genetically, yet high RTV is not a stable impairment but shows ADHD-sensitive improvement under certain conditions, such as those with rewards. The state regulation theory proposed that the RTV difference score, which captures change from baseline to a rewarded or fast condition, specifically measures 'state regulation'. By contrast, the interpretation of RTV baseline (slow, unrewarded) scores is debated. We aimed to investigate directly the degree of phenotypic and etiological overlap between RTV baseline and RTV difference scores. Method We conducted genetic model fitting analyses on go/no-go and fast task RTV data, across task conditions manipulating rewards and event rate, from a population-based twin sample (n=1314) and an ADHD and control sibling-pair sample (n=1265). RESULTS: Phenotypic and genetic/familial correlations were consistently high (0.72-0.98) between RTV baseline and difference scores, across tasks, manipulations and samples. By contrast, correlations were low between RTV in the manipulated condition and difference scores. A comparison across two different go/no-go task RTV difference scores (slow-fast/slow-incentive) showed high phenotypic and genetic/familial overlap (r = 0.75-0.83). CONCLUSIONS: Our finding that RTV difference scores measure largely the same etiological process as RTV under baseline condition supports theories emphasizing the malleability of the observed high RTV. Given the statistical shortcomings of difference scores, we recommend the use of RTV baseline scores for most analyses, including genetic analyses.

How common are motor problems in children with a developmental disorder: rule or exception?

BACKGROUND: Few co-morbidity studies have been conducted since the Leeds Consensus Statement on developmental co-ordination disorder (DCD) in 2006. In this Statement, international cut-offs and inclusion criteria were agreed and consequently, the status of DCD changed. Furthermore, most existing co-morbidity studies are small clinical studies, rather than epidemiological studies, resulting in a broad range of co-morbidity rates. DCD has a higher incidence for boys in comparison with girls; questions arise if this preponderance remains the same in combination with other developmental disorders. Therefore, in this study we aimed to determine co-morbidity and gender differences of motor problems in children with a pervasive developmental disorder, a hyperkinetic disorder and/or a speech, language or learning disability. METHODS: Profiles of 3608 children (mean age: 9 years 1 month) referred to rehabilitation centres for behavioural, developmental and sensorineural disorders were studied. RESULTS: Motor problems were reported in one-fifth of the total sample. Co-morbidity of motor problems in specific disorders varied from almost one-fourth to more than one-third. The male/female ratio was significantly higher in children with motor problems and two or more other disorders, compared with children with motor problems and less than two other disorders. CONCLUSIONS: This study indicates that co-morbidity of motor problems with other clinical disorders is not exceptional and developmental deviance is seldom specific to one domain. However, current co-morbidity studies tend to overestimate the number of children with motor problems. In addition, there may be different patterns of symptoms between the genders. These findings stress the importance of assessing motor skills in children with various developmental disorders.

'The overall quality of my life as a sibling is all right, but of course, it could always be better'. Quality of life of siblings of children with intellectual disability: the siblings' perspectives.

BACKGROUND: The concept of family quality of life is becoming increasingly important in family support programmes. This concept describes the quality of life of all family members and the family system as a whole, but only the opinion of the parents has been included. The opinion of the siblings has been incorporated in the opinions of the parents, although research has shown that there is discordance between parents' and siblings' reports. The principal goal of this study is to investigate how young siblings of children with intellectual disability define their quality of life as a sibling. METHOD: As we were more concerned with understanding the experience of being a sibling from the siblings' own frame of reference, we opted for a qualitative research design and more specifically used in-depth, phenomenology-based interviews. Data were sorted by means of a process of continuously comparing the codes according to the principles of grounded theory. RESULTS: Siblings described the following nine domains as domains of sibling quality of life: joint activities, mutual understanding, private time, acceptance, forbearance, trust in well-being, exchanging experiences, social support and dealing with the outside world. CONCLUSIONS: This study shows not only that siblings can define their quality of life, but also that this definition of sibling quality of life differs from the family quality of life concept. Therefore, it may be not only a valuable addition to the family quality of life concept but also an appropriate concept to describe siblings' experience.

The relationship between ADHD and key cognitive phenotypes is not mediated by shared familial effects with IQ.

BACKGROUND: Twin and sibling studies have identified specific cognitive phenotypes that may mediate the association between genes and the clinical symptoms of attention deficit hyperactivity disorder (ADHD). ADHD is also associated with lower IQ scores. We aimed to investigate whether the familial association between measures of cognitive performance and the clinical diagnosis of ADHD is mediated through shared familial influences with IQ. METHOD: Multivariate familial models were run on data from 1265 individuals aged 6-18 years, comprising 920 participants from ADHD sibling pairs and 345 control participants. Cognitive assessments included a four-choice reaction time (RT) task, a go/no-go task, a choice-delay task and an IQ assessment. The analyses focused on the cognitive variables of mean RT (MRT), RT variability (RTV), commission errors (CE), omission errors (OE) and choice impulsivity (CI). RESULTS: Significant familial association (rF) was confirmed between cognitive performance and both ADHD (rF=0.41-0.71) and IQ (rF=-0.25 to -0.49). The association between ADHD and cognitive performance was largely independent (80-87%) of any contribution from etiological factors shared with IQ. The exception was for CI, where 49% of the overlap could be accounted for by the familial variance underlying IQ. CONCLUSIONS: The aetiological factors underlying lower IQ in ADHD seem to be distinct from those between ADHD and RT/error measures. This suggests that lower IQ does not account for the key cognitive impairments observed in ADHD. The results have implications for molecular genetic studies designed to identify genes involved in ADHD.

Predictability of oppositional defiant disorder and symptom dimensions in children and adolescents with ADHD combined type.

BACKGROUND: Oppositional defiant disorder (ODD) is frequently co-occurring with attention deficit hyperactivity disorder (ADHD) in children and adolescents. Because ODD is a precursor of later conduct disorder (CD) and affective disorders, early diagnostic identification is warranted. Furthermore, the predictability of three recently confirmed ODD dimensions (ODD-irritable, ODD-headstrong and ODD-hurtful) may assist clinical decision making. METHOD: Receiver-operating characteristic (ROC) analysis was used in order to test the diagnostic accuracy of the Conners' Parent Rating Scale revised (CPRS-R) and the parent version of the Strength and Difficulties Questionnaire (PSDQ) in the prediction of ODD in a transnational sample of 1093 subjects aged 5-17 years from the International Multicentre ADHD Genetics study. In a second step, the prediction of three ODD dimensions by the same parent rating scales was assessed by backward linear regression analyses. RESULTS: ROC analyses showed adequate diagnostic accuracy of the CPRS-R and the PSDQ in predicting ODD in this ADHD sample. Furthermore, the three-dimensional structure of ODD was confirmed by confirmatory factor analysis and the CPRS-R emotional lability scale significantly predicted the ODD irritable dimension. CONCLUSIONS: The PSDQ and the CPRS-R are both suitable screening instruments in the identification of ODD. The emotional lability scale of the CPRS-R is an adequate predictor of irritability in youth referred for ADHD.

ADHD and DAT1: further evidence of paternal over-transmission of risk alleles and haplotype.

We [Hawi et al. (2005); Am J Hum Genet 77:958-965] reported paternal over-transmission of risk alleles in some ADHD-associated genes. This was particularly clear in the case of the DAT1 3'-UTR VNTR. In the current investigation, we analyzed three new sample comprising of 1,248 ADHD nuclear families to examine the allelic over-transmission of DAT1 in ADHD. The IMAGE sample, the largest of the three-replication samples, provides strong support for a parent of origin effect for allele 6 and the 10 repeat allele (intron 8 and 3'-UTR VNTR, respectively) of DAT1. In addition, a similar pattern of over-transmission of paternal risk haplotypes (constructed from the above alleles) was also observed. Some support is also derived from the two smaller samples although neither is independently significant. Although the mechanism driving the paternal over-transmission of the DAT risk alleles is not known, these finding provide further support for this phenomenon.

ERP correlates of error monitoring in adult ADHD.

The purpose of the current study was to evaluate whether error monitoring difficulties persist in adults with attention deficit hyperactivity disorder (ADHD) using the event-related potential (ERP) methodology. Adults with ADHD and age-matched healthy controls executed a visual Go/No-Go task with 25% No-Go trials. Performance and ERP correlates of error monitoring were compared between groups. At the performance level no difference was noted between groups. However, exploring the error-related potentials revealed that the error-related negativity (ERN) was the same for both groups, but that adults with ADHD showed a smaller error positivity (Pe). Based on these findings, we conclude that adults with ADHD are normal in early automatic error detection, but are deviant in later conscious evaluation of the error. The findings add to the increasing evidence supporting disturbances in error monitoring in ADHD and show that these problems may persist in adulthood ADHD.

Replication of a rare protective allele in the noradrenaline transporter gene and ADHD.

Replication is a key to resolving whether a reported genetic association represents a false positive finding or an actual genetic risk factor. In a previous study screening 51 candidate genes for association with ADHD in a multi-centre European sample (the IMAGE project), two single nucleotide polymorphisms (SNPs) within the norepinephrine transporter (SLC6A2) gene were found to be associated with attention deficit hyperactivity disorder (ADHD). The same SNP alleles were also reported to be associated with ADHD in a separate study from the Massachusetts General Hospital in the US. Using two independent samples of ADHD DSM-IV combined subtype trios we attempted to replicate the reported associations with SNPs rs11568324 and rs3785143 in SLC6A2. Significant association of the two markers was not observed in the two independent replication samples. However, across all four datasets the overall evidence of association with ADHD was significant (for SNP rs11568324 P = 0.0001; average odds ratio = 0.33; for SNP rs3785143 P = 0.008; average odds ratio = 1.3). The data were consistent for rs11568324, suggesting the existence of a rare allele conferring protection for ADHD within the SLC6A2 gene. Further investigations should focus on identifying the mechanisms underlying the protective effect.

Association of ADHD with genetic variants in the 5'-region of the dopamine transporter gene: evidence for allelic heterogeneity.

Multiple studies have reported an association between attention deficit hyperactivity disorder (ADHD) and the 10-repeat allele of a variable number tandem repeat (VNTR) polymorphism in the 3'-untranslated region (3'UTR) of the dopamine transporter gene (DAT1). Yet, recent meta-analyses of available data find little or no evidence for this association; although there is strong evidence for heterogeneity between datasets. This pattern of findings could arise for several reasons including the presence of relatively rare risk alleles on common haplotype backgrounds or the functional interaction of two or more loci within the gene. We previously described the importance of a specific haplotype at the 3' end of DAT1, as well as the identification of associated single nucleotide polymorphisms (SNPs) within or close to 5' regulatory sequences. In this study we replicate the association of SNPs at the 5' end of the gene and identify a specific risk haplotype spanning the 5' and 3' markers. These findings indicate the presence of at least two loci associated with ADHD within the DAT1 gene and suggest that either additive or interaction effects of these two loci on the risk for ADHD. Overall these data provide further evidence that genetic variants of the dopamine transporter gene confer an increased risk for ADHD.

No association between two polymorphisms of the serotonin transporter gene and combined type attention deficit hyperactivity disorder.

Several independent studies have reported association between serotonin transporter gene (SLC6A4) polymorphisms and attention deficit hyperactivity disorder (ADHD). Five studies found evidence for association between the long-allele of a 44-bp insertion/deletion polymorphism (5-HTTLPR) and ADHD. Another two studies corroborated this finding while a further six studies did not find such an association. For a second polymorphism within the gene, a variable number tandem repeat (VNTR) within intron 2, one study demonstrated that the 12/12 genotype was significantly less frequent in ADHD cases compared to controls, while a second study found that the 12-allele was preferentially transmitted to offspring affected with ADHD. To provide further clarification of the reported associations, we investigated the association of these two markers with ADHD in a sample of 1,020 families with 1,166 combined type ADHD cases for the International Multi-Centre ADHD Genetics project, using the Transmission Disequilibrium Test. Given the large body of work supporting the association of the promoter polymorphism and mood disorders, we further analyzed the group of subjects with ADHD plus mood disorder separately. No association was found between either of the two markers and ADHD in our large multisite study or with depression within the sample of ADHD cases.

Co-transmission of conduct problems with attention-deficit/hyperactivity disorder: familial evidence for a distinct disorder.

Common disorders of childhood and adolescence are attention-deficit/hyperactivity disorder (ADHD), oppositional defiant disorder (ODD) and conduct disorder (CD). For one to two cases in three diagnosed with ADHD the disorders may be comorbid. However, whether comorbid conduct problems (CP) represents a separate disorder or a severe form of ADHD remains controversial. We investigated familial recurrence patterns of the pure or comorbid condition in families with at least two children and one definite case of DSM-IV ADHDct (combined-type) as part of the International Multicentre ADHD Genetics Study (IMAGE). Using case diagnoses (PACS, parental account) and symptom ratings (Parent/Teacher Strengths and Difficulties [SDQ], and Conners Questionnaires [CPTRS]) we studied 1009 cases (241 with ADHDonly and 768 with ADHD + CP), and their 1591 siblings. CP was defined as > or =4 on the SDQ conduct-subscale, and T > or = 65, on Conners' oppositional-score. Multinomial logistic regression was used to ascertain recurrence risks of the pure and comorbid conditions in the siblings as predicted by the status of the cases. There was a higher relative risk to develop ADHD + CP for siblings of cases with ADHD + CP (RRR = 4.9; 95%CI: 2.59-9.41); p < 0.001) than with ADHDonly. Rates of ADHDonly in siblings of cases with ADHD + CP were lower but significant (RRR = 2.9; 95%CI: 1.6-5.3, p < 0.001). Children with ADHD + CP scored higher on the Conners ADHDct symptom-scales than those with ADHDonly. Our finding that ADHD + CP can represent a familial distinct subtype possibly with a distinct genetic etiology is consistent with a high risk for cosegregation. Further, ADHD + CP can be a more severe disorder than ADHDonly with symptoms stable from childhood through adolescence. The findings provide partial support for the ICD-10 distinction between hyperkinetic disorder (F90.0) and hyperkinetic conduct disorder (F90.1).

A high-density SNP linkage scan with 142 combined subtype ADHD sib pairs identifies linkage regions on chromosomes 9 and 16.

As part of the International Multi-centre ADHD Genetics project we completed an affected sibling pair study of 142 narrowly defined Diagnostic and Statistical Manual of Mental Disorders, fourth edition combined type attention deficit hyperactivity disorder (ADHD) proband-sibling pairs. No linkage was observed on the most established ADHD-linked genomic regions of 5p and 17p. We found suggestive linkage signals on chromosomes 9 and 16, respectively, with the highest multipoint nonparametric linkage signal on chromosome 16q23 at 99 cM (log of the odds, LOD=3.1) overlapping data published from the previous UCLA (University of California, Los Angeles) (LOD>1, approximately 95 cM) and Dutch (LOD>1, approximately 100 cM) studies. The second highest peak in this study was on chromosome 9q22 at 90 cM (LOD=2.13); both the previous UCLA and German studies also found some evidence of linkage at almost the same location (UCLA LOD=1.45 at 93 cM; German LOD=0.68 at 100 cM). The overlap of these two main peaks with previous findings suggests that loci linked to ADHD may lie within these regions. Meta-analysis or reanalysis of the raw data of all the available ADHD linkage scan data may help to clarify whether these represent true linked loci.