Emotional lability (EL) is commonly seen in patients with Attention Deficit/Hyperactivity Disorder (ADHD). The reasons for this association are currently unknown. To address this question we examined the relationship between ADHD and EL symptoms, and performance on a range of neuropsychological tasks to clarify whether EL symptoms are predicted by particular cognitive and/or motivational dysfunctions and whether these associations are mediated by the presence of ADHD symptoms.
A large multi-site sample of 424 carefully diagnosed ADHD cases and 564 unaffected siblings and controls aged 6 to 18 years performed a broad neuropsychological test battery, including a Go/No-Go Task, a warned 4-choice Reaction Time task, the Maudsley Index of Childhood Delay Aversion, and Digit span backwards. Neuropsychological variables were aggregated as indices of processing speed, response variability, executive functions, choice impulsivity and the influence of energetic and/or motivational factors.
EL and ADHD symptoms were regressed on each neuropsychological variable in separate analyses controlling for age, gender and IQ, and, in subsequent regression analyses, for ADHD and EL symptoms respectively.
Neuropsychological variables significantly predicted ADHD and EL symptoms with moderate to low regression coefficients. However, the association between neuropsychological parameters on EL disappeared entirely when the effect of ADHD symptoms was taken into account, revealing that the association between the neuropsychological performance measures and EL is completely mediated statistically by variations in ADHD symptoms. Conversely, neuropsychological effects on ADHD symptoms remained after EL symptom severity was taken into account.
The neuropsychological parameters examined here predict ADHD more strongly than EL. They cannot explain EL symptoms beyond what is already accounted for by ADHD symptom severity. The association between EL and ADHD cannot be explained by these cognitive or motivational deficits. Alternative mechanisms, including overlapping genetic influences (pleiotropic effects), and/or alternative neuropsychological processes need to be considered.
ADHD; neuropsychological performance; emotional lability; executive functions; delay aversion
Autism spectrum disorders (ASDs) are associated with auditory hyper- or hyposensitivity; atypicalities in central auditory processes, such as speech-processing and selective auditory attention; and neural connectivity deficits. We sought to investigate whether the low-level integrative processes underlying sound localization and spatial discrimination are affected in ASDs.
We performed 3 behavioural experiments to probe different connecting neural pathways: 1) horizontal and vertical localization of auditory stimuli in a noisy background, 2) vertical localization of repetitive frequency sweeps and 3) discrimination of horizontally separated sound stimuli with a short onset difference (precedence effect).
Ten adult participants with ASDs and 10 healthy control listeners participated in experiments 1 and 3; sample sizes for experiment 2 were 18 adults with ASDs and 19 controls. Horizontal localization was unaffected, but vertical localization performance was significantly worse in participants with ASDs. The temporal window for the precedence effect was shorter in participants with ASDs than in controls.
The study was performed with adult participants and hence does not provide insight into the developmental aspects of auditory processing in individuals with ASDs.
Changes in low-level auditory processing could underlie degraded performance in vertical localization, which would be in agreement with recently reported changes in the neuroanatomy of the auditory brainstem in individuals with ASDs. The results are further discussed in the context of theories about abnormal brain connectivity in individuals with ASDs.
Twin studies using both clinical and population-based samples suggest that the frequent co-occurrence of attention deficit hyperactivity disorder (ADHD) and reading ability/disability (RD) is largely driven by shared genetic influences. While both disorders are associated with lower IQ, recent twin data suggest that the shared genetic variability between reading difficulties and ADHD inattention symptoms is largely independent from genetic influences contributing to general cognitive ability. The current study aimed to extend the previous findings that were based on rating scale measures in a population sample by examining the generalizability of the findings to a clinical population, and by measuring reading difficulties both with a rating scale and with an objective task. We therefore investigated the familial relationships between ADHD, reading difficulties and IQ in a sample of individuals diagnosed with ADHD combined type, their siblings and control sibling pairs.
We ran multivariate familial models on data from 1789 individuals at ages 6 to 19. Reading difficulties were measured with both rating scale and an objective task. IQ was obtained using the Wechsler Intelligence Scales (WISC-III / WAIS-III).
Significant phenotypic (0.2–0.4) and familial (0.3–0.5) correlations were observed among ADHD, reading difficulties and IQ. Yet 53% to 72% of the overlapping familial influences between ADHD and reading difficulties were not shared with IQ.
Our finding that familial influences shared with general cognitive ability, though present, do not account for the majority of the overlapping familial influences on ADHD and reading difficulties extends previous findings from a population-based study to a clinically-ascertained sample with combined type ADHD.
ADHD; reading difficulties; IQ; familial; sibling-pair; comorbidity
To compile an inventory of European healthcare databases with potential to study long-term effects of methylphenidate (MPH) in patients with attention deficit hyperactivity disorder (ADHD). Potential databases were identified through expert opinion, the website of the European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, and literature search. An online survey was conducted among database providers/coordinators to ascertain the databases’ appropriateness for inclusion into the inventory. It included questions about database characteristics, sample size, availability of information on drug exposure, clinical data and accessibility. Forty-two databases from 11 countries were identified and their coordinators invited to participate; responses were obtained for 22 (52.4 %) databases of which 15 record ADHD diagnoses. Eleven had sufficient data on ADHD diagnosis, drug exposure, and at least one type of outcome information (symptoms/clinical events, weight, height, blood pressure, heart rate) to assess MPH safety. These were Aarhus University Prescription Database, Danish National Birth Cohort (Denmark); German Health Interview and Examination Survey for Children and Adolescents; Health Search Database Thales, Italian ADHD Register, Lombardy Region ADHD Database (Italy); Avon Longitudinal Study of Parents and Children, General Practice Research Database, The Health Improvement Network, QResearch (UK) and IMS Disease Analyzer (UK, Germany, France). Of the 20 databases with no responses, information on seven from publications and/or websites was obtained; Pedianet and the Integrated Primary Care Information database were considered suitable. Many European healthcare databases can be used for multinational long-term safety studies of MPH. Methodological research is underway to investigate the feasibility of their pooling and analysis.
Database(s); Methylphenidate; Attention deficit hyperactivity disorder (ADHD); Drug safety; Paediatric
The neurotransmitter dopamine plays a key role in cognitive functions that are associated with fronto-striatal circuitry and has been implicated in many neuropsychiatric disorders. However, there is a large variability in the direction and extent of dopaminergic drug effects across individuals.
We investigated whether individual differences in dopaminergic drug effects on human fronto-striatal functioning are associated with individual differences in white matter tracts.
The effects of the dopamine receptor agonist bromocriptine were assessed using functional magnetic resonance imaging in 22 healthy volunteers in a placebo-controlled, double-blind, within-subject design. Human psychopharmacology and functional neuroimaging were combined with functional connectivity analyses and structural connectivity analyses to establish a link between dopaminergic drug effects on fronto-striatal function and fronto-striatal anatomy.
We demonstrate that bromocriptine alters functional signals associated with attention switching in the basal ganglia. Crucially, individual differences in the drug’s effect on these signals could be predicted from individual differences in fronto-striato-thalamic white matter tracts, as indexed by diffusion tensor imaging. Anatomical fronto-striatal connectivity also predicted drug effects on switch-related functional connectivity between the basal ganglia and the prefrontal cortex.
These data reinforce the link between dopamine, cognition and the basal ganglia and have implications for the individual tailoring of dopaminergic drug therapy based on anatomical fronto-striatal connection strength.
Electronic supplementary material
The online version of this article (doi:10.1007/s00213-013-3000-5) contains supplementary material, which is available to authorized users.
Prefrontal cortex; Attention; Basal ganglia; Connectivity; Dopamine; fMRI
Dopamine in the striatum is known to be important for reversal learning. However, the striatum does not act in isolation and reversal learning is also well-accepted to depend on the orbitofrontal cortex (OFC) and the amygdala. Here we assessed whether dopaminergic drug effects on human striatal BOLD signaling during reversal learning is associated with anatomical connectivity in an orbitofrontal-limbic-striatal network, as measured with diffusion tensor imaging (DTI). By using a fiber-based approach, we demonstrate that dopaminergic drug effects on striatal BOLD signal varied as a function of fractional anisotropy (FA) in a pathway connecting the OFC with the amygdala. Moreover, our experimental design allowed us to establish that these white-matter dependent drug effects were mediated via D2 receptors. Thus, white matter dependent effects of the D2 receptor agonist bromocriptine on striatal BOLD signal were abolished by co-administration with the D2 receptor antagonist sulpiride. These data provide fundamental insight into the mechanism of action of dopaminergic drug effects during reversal learning. In addition, they may have important clinical implications by suggesting that white matter integrity can help predict dopaminergic drug effects on brain function, ultimately contributing to individual tailoring of dopaminergic drug treatment strategies in psychiatry.
dopamine; striatum; amygdala; OFC; reversal learning; diffusion tensor imaging; bromocriptine; sulpiride
Recent studies have emphasized an important role for long non-coding RNAs (lncRNA) in epigenetic regulation, development, and disease. Despite growing interest in lncRNAs, the mechanisms by which lncRNAs control cellular processes are still elusive. Improved understanding of these mechanisms is critical, because the majority of the mammalian genome is transcribed, in most cases resulting in non-coding RNA products. Recent studies have suggested the involvement of lncRNA in neurobehavioral and neurodevelopmental disorders, highlighting the functional importance of this subclass of brain-enriched RNAs. Impaired expression of lnRNAs has been implicated in several forms of intellectual disability disorders. However, the role of this family of RNAs in cognitive function is largely unknown. Here we provide an overview of recently identified mechanisms of neuronal development involving lncRNAs, and the consequences of lncRNA deregulation for neurodevelopmental disorders.
long non-coding RNA; nervous system development; fragile X syndrome; genomic imprinting; autism spectrum disorders; intellectual disability; schizophrenia
Recent studies have shown that while psychopathy and non-psychopathic antisociality overlap, they differ in the extent to which cognitive impairments are present. Specifically, psychopathy has been related to abnormal allocation of attention, a function that is traditionally believed to be indexed by event-related potentials (ERPs) of the P3-family. Previous research examining psychophysiological correlates of attention in psychopathic individuals has mainly focused on the parietally distributed P3b component to rare targets. In contrast, very little is known about the frontocentral P3a to infrequent novel events in psychopathy. Thus, findings on the P3 components in psychopathy are inconclusive, while results in non-psychopathic antisocial populations are clearer and point toward an inverse relationship between antisociality and P3 amplitudes. The present study adds to extant literature on the P3a and P3b in psychopathy by investigating component amplitudes in psychopathic offenders (N = 20), matched non-psychopathic offenders (N = 23) and healthy controls (N = 16). Also, it was assessed how well each offender group was able to differentially process rare novel and target events. The offender groups showed general amplitude reductions compared to healthy controls, but did not differ mutually on overall P3a/P3b amplitudes. However, the psychopathic group still exhibited normal neurophysiological differentiation when allocating attention to rare novel and target events, unlike the non-psychopathic sample. The results highlight differences between psychopathic and non-psychopathic offenders regarding the integrity of the neurocognitive processes driving attentional allocation, as well as the usefulness of alternative psychophysiological measures in differentiating psychopathy from general antisociality.
Psychologists, with their long-standing tradition of studying mechanistic processes, can make important contributions to further characterizing the risk associated with genes identified as influencing risk for psychiatric disorders. We report one such effort with respect to CHRM2, which codes for the cholinergic muscarinic 2 receptor and was of interest originally for its association with alcohol dependence. We tested for association between CHRM2 and prospectively measured externalizing behavior in a longitudinal, community-based sample of adolescents, as well as for moderation of this association by parental monitoring. We found evidence for an interaction in which the association between the genotype and externalizing behavior was stronger in environments with lower parental monitoring. There was also suggestion of a crossover effect, in which the genotype associated with the highest levels of externalizing behavior under low parental monitoring had the lowest levels of externalizing behavior at the extreme high end of parental monitoring. The difficulties involved in distinguishing mechanisms of gene-environment interaction are discussed.
adolescent development; genetics; behavior genetics; drug/substance abuse; antisocial behavior
For clinically referred children with Autism Spectrum Disorder (ASD) or Attention Deficit/Hyperactivity Disorder (ADHD) several early indicators have been described. However, knowledge is lacking on early markers of less severe variants of ASD and ADHD from the general population. The aim of the present study is to identify early indicators of high risk groups for ASD and ADHD problems based on routine data from community pediatric services between infancy and age four. Data are from 1,816 participants who take part in Tracking Adolescents’ Individual Lives Survey (TRAILS), a longitudinal study. Information on early developmental factors was extracted from charts of routine Preventive Child Healthcare (PCH) visits. To assess ASD and ADHD problems, respectively, we used the Children’s Social Behavior Questionnaire (CSBQ) and the Child Behavior Checklist (CBCL), filled out by parents three times between the ages of 11 and 17. Note that these are parent ratings and not diagnostic instruments performed by trained clinicians. Male gender, low birth weight, low level of education of the mother, social, behavioral, language, psychomotor and eating problems significantly predicted ASD problems (odds ratios (OR) between 1.34 and 2.41). ADHD problems were also predicted by male gender and low level of education of the mother and by maternal smoking during pregnancy, good gross motor skills in first year, early attention and hyperactivity problems, and absence of parent-reported positive behavior (ORs between 1.36 and 1.74). Routine data on early childhood from PCH services are predictive for ASD and ADHD problems in adolescents in the general population. The PCH services are a useful setting to identify high risk groups, and to monitor them subsequently.
Autism; ADHD; Risk factors; Longitudinal studies; Child development
Callous–unemotional (CU) traits are currently viewed as the defining signs and symptoms of juvenile psychopathy. It is unclear, however, whether CU traits have validity only in the context of conduct disorder (CD) as proposed by Frick and Moffitt (A proposal to the DSM-V childhood disorders and the ADHD and disruptive behavior disorders work groups to include a specifier to the diagnosis of conduct disorder based on the presence of callous–unemotional traits, American Psychiatric Association, Washington, DC, 2010), or also outside CD, either in combination with other forms of psychopathology or as a stand-alone construct.
The current review systematically studied the existent literature on CU traits in juveniles to examine their validity inside and outside CD according to the framework regarding the validity of a psychiatric diagnosis provided by Robins and Guze (Am J Psychiatry 126:983–987, 1970).
Inside youth with conduct problems, and CD specifically, it seems that CU traits meet the Robins and Guze criteria. As many of the reviewed studies included youth with ODD and ADHD as well, there are indications the same might be true for ODD and ADHD, although probably to a lesser extent. In other disorders, CU traits may be present as well, but their role is not firmly established. As stand-alone construct, data are lacking or are scarce on all of the above-mentioned criteria.
CU traits are a useful specifier in CD, and possibly also in disruptive behaviour disorders (DBDs) more generally. High CU traits outside DBDs exist but it is as yet unknown if there is a clinical need for defining CU traits as a stand-alone construct.
Callous–unemotional traits; Juvenile psychopathy; Conduct disorder; Validity
It is unclear whether symptoms of autism spectrum disorder (ASD) in young children in the population fit the three-factor structure of ASD as described in the DSM-IV, and cluster together in individual subjects. This study analysed questionnaire data on ASD symptoms filled in by mothers of 11,332 18-month-old children that was collected in the context of the Norwegian Mother and Child Cohort Study conducted by the Norwegian Institute of Public Health. Confirmatory Factor Analyses showed that the three-factor model had a significantly better fit then the two- and one-factor model of ASD symptoms. Latent class analysis revealed four homogeneous groups of children (classes) with different scores for Social Interaction and Communication at one hand and Stereotypies/Rigidity at the other hand.
Autism spectrum disorders; Symptom domains; General population; Infants; MoBa; Confirmatory factor analysis (CFA); Latent class analysis (LCA)
This study of gaze patterns in very young children with autism and their parents included 23 cases (with 16 fathers and 19 mothers) and 46 controls (with 14 fathers and 28 mothers). Children (mean age 3.3 ± 1.5
years) with autism met DSM-IV and ADOS-G diagnostic criteria. The participants' gaze patterns were recorded while they viewed four simple movies that did not feature people. In children, severity of autism is related to spending more time watching irrelevant regions in one of the four movies. The mothers of children with autism showed an atypical pattern for three movies, whereas the fathers of children with autism did not show an atypical gaze pattern. The gaze pattern of the mothers was positively correlated with that of their children. The atypical viewing pattern of autistic individuals appears not to be restricted to people and social situations but is also seen in other situations, suggesting that there is a perceptual broad autism phenotype.
The present study examines the relationship between neurocognitive functioning and affective problems through adolescence, in a cross-sectional and longitudinal perspective. Baseline response speed, response speed variability, response inhibition, attentional flexibility and working memory were assessed in a cohort of 2,179 adolescents (age 10–12 years) from the TRacking Adolescents’ Individual Lives Survey (TRAILS). Affective problems were measured with the DSM-oriented Affective Problems scale of the Youth Self Report at wave 1 (baseline assessment), wave 2 (after 2.5 years) and wave 3 (after 5 years). Cross-sectionally, baseline response speed, response time variability, response inhibition and working memory were associated with baseline affective problems in girls, but not in boys. Longitudinally, enhanced response time variability predicted affective problems after 2.5 and 5 years in girls, but not in boys. Decreased response inhibition predicted affective problems after 5 years follow-up in girls, and again not in boys. The results are discussed in light of recent insights in gender differences in adolescence and state–trait issues in depression.
Depression; Affective problems; Neuropsychology; Gender; Adolescence; Cohort; Medicine & Public Health; Psychiatry
Brain-derived neurotrophic factor (BDNF) is involved in major depressive disorder and neurodegenerative diseases. Clinical studies, showing decreased serum BDNF levels, are difficult to interpret due to limited knowledge of potential confounders and mixed results for age and sex effects. We explored potential determinants of serum BDNF levels in a community sample of 1230 subjects.
Multiple linear regression analyses with serum BDNF level as the dependent variable were conducted to explore the effect of four categories of potential BDNF determinants (sampling characteristics, sociodemographic variables, lifestyle factors and somatic diseases) and of self-reported depressive symptoms (Beck's Depression Inventory (BDI).
Our results show that BDNF levels decline with age in women, whereas in men levels remain stable. Moreover, after controlling for age and gender, the assays still showed lower serum BDNF levels with higher BDI sum scores. Effects remained significant after correction for two main confounders (time of sampling and smoking), suggesting that they serve as molecular trait factors independent of lifestyle factors.
Given the age-sex interaction on serum BDNF levels and the known association between BDNF and gonadal hormones, research is warranted to delineate the effects of the latter interaction on the risk of psychiatric and neurodegenerative diseases.
Depression; neurodegenerative disease; brain-derived neurotrophic factor (BDNF); age; gender
In recent years, there has been growing enthusiasm that functional magnetic resonance imaging (MRI) could achieve clinical utility for a broad range of neuropsychiatric disorders. However, several barriers remain. For example, the acquisition of large-scale datasets capable of clarifying the marked heterogeneity that exists in psychiatric illnesses will need to be realized. In addition, there continues to be a need for the development of image processing and analysis methods capable of separating signal from artifact. As a prototypical hyperkinetic disorder, and movement-related artifact being a significant confound in functional imaging studies, ADHD offers a unique challenge. As part of the ADHD-200 Global Competition and this special edition of Frontiers, the ADHD-200 Consortium demonstrates the utility of an aggregate dataset pooled across five institutions in addressing these challenges. The work aimed to (1) examine the impact of emerging techniques for controlling for “micro-movements,” and (2) provide novel insights into the neural correlates of ADHD subtypes. Using support vector machine (SVM)-based multivariate pattern analysis (MVPA) we show that functional connectivity patterns in individuals are capable of differentiating the two most prominent ADHD subtypes. The application of graph-theory revealed that the Combined (ADHD-C) and Inattentive (ADHD-I) subtypes demonstrated some overlapping (particularly sensorimotor systems), but unique patterns of atypical connectivity. For ADHD-C, atypical connectivity was prominent in midline default network components, as well as insular cortex; in contrast, the ADHD-I group exhibited atypical patterns within the dlPFC regions and cerebellum. Systematic motion-related artifact was noted, and highlighted the need for stringent motion correction. Findings reported were robust to the specific motion correction strategy employed. These data suggest that resting-state functional connectivity MRI (rs-fcMRI) data can be used to characterize individual patients with ADHD and to identify neural distinctions underlying the clinical heterogeneity of ADHD.
ADHD; functional connectivity; support vector machines; RDoC; research domain criteria
Symptoms of Autism Spectrum Disorder (ASD) and Attention-Deficit/Hyperactivity Disorder (ADHD) often co-occur. Given the previously found familiality of ASD symptoms in children with ADHD, addressing these symptoms may be useful for genetic association studies, especially for candidate gene findings that have not been consistently replicated for ADHD.
We studied the association of the catechol o-methyltransferase (COMT) Val158Met polymorphism and the serotonin transporter (SLC6A4/SERT/5-HTT) 5-HTTLPR insertion/deletion polymorphism with ASD symptoms in children with ADHD, and whether these polymorphisms would interact with pre- and perinatal risk factors, i.e., maternal smoking during pregnancy and low birth weight. Analyses were performed using linear regression in 207 Dutch participants with combined type ADHD of the International Multicenter ADHD Genetics (IMAGE) study, and repeated in an independent ADHD sample (n = 439) selected from the TRracking Adolescents' Individual Lives Survey (TRAILS). Dependent variables were the total and subscale scores of the Children's Social Behavior Questionnaire (CSBQ).
No significant main effects of COMT Val158Met, 5-HTTLPR, maternal smoking during pregnancy and low birth weight on ASD symptoms were found. However, the COMT Val/Val genotype interacted with maternal smoking during pregnancy in increasing stereotyped behavior in the IMAGE sample (p = 0.008); this interaction reached significance in the TRAILS sample after correction for confounders (p = 0.02). In the IMAGE sample, the 5-HTTLPR S/S genotype interacted with maternal smoking during pregnancy, increasing problems in social interaction (p = 0.02), and also interacted with low birth weight, increasing rigid behavior (p = 0.03). Findings for 5-HTTLPR in the TRAILS sample were similar, albeit for related CSBQ subscales.
These findings suggest gene-environment interaction effects on ASD symptoms in children with ADHD.
Attention-deficit/Hyperactivity Disorder; Autism Spectrum Disorder; gene environment; 5-HTT; COMT
The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with the combined type of attention deficit/hyperactivity disorder (ADHD-CT) and 1446 'unselected' siblings. The aim was to analyse the IMAGE sample with respect to demographic features (gender, age, family status, and recruiting centres) and psychopathological characteristics (diagnostic subtype, symptom frequencies, age at symptom detection, and comorbidities). A particular focus was on the effects of the study design and the diagnostic procedure on the homogeneity of the sample in terms of symptom-based behavioural data, and potential consequences for further analyses based on these data.
Diagnosis was based on the Parental Account of Childhood Symptoms (PACS) interview and the DSM-IV items of the Conners' teacher questionnaire. Demographics of the full sample and the homogeneity of a subsample (all probands) were analysed by using robust statistical procedures which were adjusted for unequal sample sizes and skewed distributions. These procedures included multi-way analyses based on trimmed means and winsorised variances as well as bootstrapping.
Age and proband/sibling ratios differed between participating centres. There was no significant difference in the distribution of gender between centres. There was a significant interaction between age and centre for number of inattentive, but not number of hyperactive symptoms. Higher ADHD symptom frequencies were reported by parents than teachers. The diagnostic symptoms differed from each other in their frequencies. The face-to-face interview was more sensitive than the questionnaire. The differentiation between ADHD-CT probands and unaffected siblings was mainly due to differences in hyperactive/impulsive symptoms.
Despite a symptom-based standardized inclusion procedure according to DSM-IV criteria with defined symptom thresholds, centres may differ markedly in probands' ADHD symptom frequencies. Both the diagnostic procedure and the multi-centre design influence the behavioural characteristics of a sample and, thus, may bias statistical analyses, particularly in genetic or neurobehavioral studies.
ADHD; multi-centre study; sibling design; ADHD; informant effects; centre effects
The International Multi-centre ADHD Genetics (IMAGE) project with 11 participating centres from 7 European countries and Israel has collected a large behavioural and genetic database for present and future research. Behavioural data were collected from 1068 probands with ADHD and 1446 unselected siblings. The aim was to describe and analyse questionnaire data and IQ measures from all probands and siblings. In particular, to investigate the influence of age, gender, family status (proband vs. sibling), informant, and centres on sample homogeneity in psychopathological measures.
Conners' Questionnaires, Strengths and Difficulties Questionnaires, and Wechsler Intelligence Scores were used to describe the phenotype of the sample. Data were analysed by use of robust statistical multi-way procedures.
Besides main effects of age, gender, informant, and centre, there were considerable interaction effects on questionnaire data. The larger differences between probands and siblings at home than at school may reflect contrast effects in the parents. Furthermore, there were marked gender by status effects on the ADHD symptom ratings with girls scoring one standard deviation higher than boys in the proband sample but lower than boys in the siblings sample. The multi-centre design is another important source of heterogeneity, particularly in the interaction with the family status. To a large extent the centres differed from each other with regard to differences between proband and sibling scores.
When ADHD probands are diagnosed by use of fixed symptom counts, the severity of the disorder in the proband sample may markedly differ between boys and girls and across age, particularly in samples with a large age range. A multi-centre design carries the risk of considerable phenotypic differences between centres and, consequently, of additional heterogeneity of the sample even if standardized diagnostic procedures are used. These possible sources of variance should be counteracted in genetic analyses either by using age and gender adjusted diagnostic procedures and regional normative data or by adjusting for design artefacts by use of covariate statistics, by eliminating outliers, or by other methods suitable for reducing heterogeneity.
ADHD; multi-centre study; sibling design; centre effects
Recent studies have reported abnormal functional connectivity patterns in the brains of people with autism that may be accompanied by decreases in white matter integrity. Since autism is a developmental disorder, we aim to investigate the nature and location of decreases in white and grey matter integrity in an adolescent sample while accounting for age.
We used structural (T1) imaging to study brain volumetrics and diffusion tensor imaging (DTI) to investigate white and grey matter integrity in people with autism. We obtained magnetic resonance images for adolescents aged 12–18 years with high-functioning autism and from matched controls. Fractional anisotropy and mean diffusivity, as well as grey and white matter volumetrics were analyzed.
There were 17 participants with autism and 25 matched controls included in this study. Participants with autism had lower fractional anisotropy in the left and right superior and inferior longitudinal fasciculus, but this effect was not significant after adjusting for age and intelligence quotient (IQ). The kurtosis of the white matter fractional anisotropy probability distribution was higher in this participant group, with and without adjustment for age and IQ. Most notably, however, the mean diffusivity levels were markedly increased in the autism group throughout the brain, and the mean diffusivity probability distributions of both grey and white matter were shifted toward a higher value, particularly with age and IQ adjustment. No volumetric differences in grey and white matter were found.
We corrected for age and IQ using a linear model. The study was also limited by its sample size, investigated age range and cross-sectional design.
The findings suggest that autism is characterized by a generalized reduction of white matter integrity that is associated with an increase of interstitial space. The generalized manifestation of the white matter abnormalities provides an important new perspective on autism as a connectivity disorder.
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.
Chronic pain; Children; Adolescents; Psychiatry