Characterizing the heterogeneous course of inattention and hyperactivity-impulsivity from childhood to young adulthood.

To advance understanding of the heterogeneity in the course of ADHD, joint symptom trajectories of inattention and hyperactivity-impulsivity from childhood to young adulthood were modelled and associated with genetic, demographic, and clinical characteristics. Data were obtained from the NeuroIMAGE cohort which includes 485 individuals with ADHD, their 665 siblings, and 399 typically developing children. Trajectories were based on scores of the Conners Parent Rating Scale Revised and estimated over seven homogeneous age bins (from 5 to 28 years) using parallel process latent class growth analysis on data collected across 2-4 time points. Multilevel multinomial logistic regression was used to identify characteristics that differentiated between the derived classes. A seven-class solution revealed "severe combined stable" (4.8%), "severe combined decreasing" (13%), "severe inattentive stable" (4.8%), "moderate combined increasing" (7.5%), "moderate combined decreasing" (12.7%), "stable mild" (12.9%), and "stable low" (44.3%) classes. Polygenic risk for depression, ADHD diagnosis, ADHD medication use, IQ, comorbid symptom levels (foremost oppositional behaviour), and functional impairment levels differentiated classes with similar ADHD symptom levels in childhood but a diverging course thereafter. The course of ADHD is highly heterogeneous, with stable, decreasing, and increasing trajectories. Overall, severe symptom levels in childhood are associated with elevated-to-severe symptom levels in adolescence and young adulthood, despite substantial symptom reductions. Beyond symptom severity in childhood, genetic, demographic, and clinical characteristics distinguish the heterogeneous course.

Analysis of structural brain asymmetries in attention-deficit/hyperactivity disorder in 39 datasets.

OBJECTIVE: Some studies have suggested alterations of structural brain asymmetry in attention-deficit/hyperactivity disorder (ADHD), but findings have been contradictory and based on small samples. Here, we performed the largest ever analysis of brain left-right asymmetry in ADHD, using 39 datasets of the ENIGMA consortium. METHODS: We analyzed asymmetry of subcortical and cerebral cortical structures in up to 1,933 people with ADHD and 1,829 unaffected controls. Asymmetry Indexes (AIs) were calculated per participant for each bilaterally paired measure, and linear mixed effects modeling was applied separately in children, adolescents, adults, and the total sample, to test exhaustively for potential associations of ADHD with structural brain asymmetries. RESULTS: There was no evidence for altered caudate nucleus asymmetry in ADHD, in contrast to prior literature. In children, there was less rightward asymmetry of the total hemispheric surface area compared to controls (t = 2.1, p = .04). Lower rightward asymmetry of medial orbitofrontal cortex surface area in ADHD (t = 2.7, p = .01) was similar to a recent finding for autism spectrum disorder. There were also some differences in cortical thickness asymmetry across age groups. In adults with ADHD, globus pallidus asymmetry was altered compared to those without ADHD. However, all effects were small (Cohen's d from -0.18 to 0.18) and would not survive study-wide correction for multiple testing. CONCLUSION: Prior studies of altered structural brain asymmetry in ADHD were likely underpowered to detect the small effects reported here. Altered structural asymmetry is unlikely to provide a useful biomarker for ADHD, but may provide neurobiological insights into the trait.

Stimulant treatment profiles predicting co-occurring substance use disorders in individuals with attention-deficit/hyperactivity disorder.

Adolescents with attention-deficit/hyperactivity disorder (ADHD) are at increased risk of developing substance use disorders (SUDs) and nicotine dependence (ND). It remains unclear whether and how stimulant treatment may affect this risk. We aimed to investigate how stimulant use profiles influence the risk of SUDs and ND, using a novel data-driven community detection analysis to construct different stimulant use profiles. Comprehensive lifetime stimulant prescription data and data on SUDs and ND were available for 303 subjects with ADHD and 219 controls, with a mean age 16.3 years. Community detection was used to define subgroups based on multiple indicators of treatment history, start age, treatment duration, total dose, maximum dose, variability, stop age. In stimulant-treated participants, three subgroups with distinct medication trajectories were distinguished (late-and-moderately dosed, n = 91; early-and-moderately dosed, n = 51; early-and-intensely dosed, n = 103). Compared to stimulant-naïve participants (n = 58), the early-and-intense treatment group had a significantly lower risk of SUDs and ND (HR = 0.28, and HR = 0.29, respectively), while the early-and-moderate group had a significantly lower risk of ND only (HR = 0.30). The late-and-moderate group was at a significantly higher risk of ND compared to the other two treatment groups (HR = 2.66 for early-and-moderate, HR = 2.78 for early-and-intense). Our findings show that in stimulant-treated adolescents with ADHD, long-term outcomes are associated with treatment characteristics, something that is often ignored when treated individuals are compared to untreated individuals.

Network-level assessment of reward-related activation in patients with ADHD and healthy individuals.

INTRODUCTION: Reward processing is a key aspect of cognitive control processes, putatively instantiated by mesolimbic and mesocortical brain circuits. Deficient signaling within these circuits has been associated with psychopathology. We applied a network discovery approach to assess specific functional networks associated with reward processing in participants with attention-deficit/hyperactivity disorder (ADHD). METHODS: To describe task-related processes in terms of integrated functional networks, we applied independent component analysis (ICA) to task response maps of 60 healthy participants who performed a monetary incentive delay (MID) task. The resulting components were interpreted on the basis of their similarity with group-level task responses as well as their similarity with brain networks derived from resting state fMRI analyses. ADHD-related effects on network characteristics including functional connectivity and communication between networks were examined in an independent sample comprising 150 participants with ADHD and 48 healthy controls. RESULTS: We identified 23 components to be associated with 4 large-scale functional networks: the default-mode, visual, executive control, and salience networks. The salience network showed a specific association with reward processing as well as the highest degree of within-network integration. ADHD was associated with decreased functional connectivity between the salience and executive control networks as well as with peripheral brain regions. CONCLUSIONS: Reward processing as measured with the MID task involves one reward-specific and three general functional networks. Participants with ADHD exhibited alterations in connectivity of both the salience and executive control networks and associated brain regions during task performance. Hum Brain Mapp 38:2359-2369, 2017. © 2017 Wiley Periodicals, Inc.

Female-specific association of NOS1 genotype with white matter microstructure in ADHD patients and controls.

BACKGROUND: The nitric oxide synthase gene (NOS1) exon 1f (ex1f) VNTR is a known genetic risk factor for Attention-Deficit/Hyperactivity Disorder (ADHD), particularly in females. NOS1 plays an important role in neurite outgrowth and may thus influence brain development, specifically white matter (WM) microstructure, which is known to be altered in ADHD. The current study aimed to investigate whether NOS1 is associated with WM microstructure in (female) individuals with and without ADHD. METHODS: Diffusion Tensor Imaging (DTI) scans were collected from 187 participants with ADHD (33% female) and 103 controls (50% female), aged 8-26 years, and NOS1-ex1f VNTR genotype was determined. Whole-brain analyses were conducted for fractional anisotropy (FA) and mean diffusivity (MD) to examine associations between NOS1 and WM microstructure, including possible interactions with gender and diagnosis. RESULTS: Consistent with previous literature, NOS1-ex1f was associated with total ADHD and hyperactivity-impulsivity symptoms, but not inattention; this effect was independent of gender. NOS1-ex1f was also associated with MD values in several major WM tracts in females, but not males. In females, homozygosity for the short allele was linked to higher MD values than carriership of the long allele. MD values in these regions did not correlate with ADHD symptoms. Results were similar for participants with and without ADHD. CONCLUSIONS: NOS1-ex1f VNTR is associated with WM microstructure in females in a large sample of participants with ADHD and healthy controls. Whether this association is part of a neurodevelopmental pathway from NOS1 to ADHD symptoms should be further investigated in future studies.

Effects of dopaminergic genes, prenatal adversities, and their interaction on attention-deficit/hyperactivity disorder and neural correlates of response inhibition.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is often accompanied by impaired response inhibition; both have been associated with aberrant dopamine signalling. Given that prenatal exposure to alcohol or smoking is known to affect dopamine-rich brain regions, we hypothesized that individuals carrying the ADHD risk alleles of the dopamine receptor D4 (DRD4) and dopamine transporter (DAT1) genes may be especially sensitive to their effects. METHODS: Functional MRI data, information on prenatal adversities and genetic data were available for 239 adolescents and young adults participating in the multicentre ADHD cohort study NeuroIMAGE (average age 17.3 yr). We analyzed the effects of DRD4 and DAT1, prenatal exposure to alcohol and smoking and their interactions on ADHD severity, response inhibition and neural activity. RESULTS: We found no significant gene × environment interaction effects. We did find that the DRD4 7-repeat allele was associated with less superior frontal and parietal brain activity and with greater activity in the frontal pole and occipital cortex. Prenatal exposure to smoking was also associated with lower superior frontal activity, but with greater activity in the parietal lobe. Further, those exposed to alcohol had more activity in the lateral orbitofrontal cortex, and the DAT1 risk variant was associated with lower cerebellar activity. LIMITATIONS: Retrospective reports of maternal substance use and the cross-sectional study design restrict causal inference. CONCLUSION: While we found no evidence of gene × environment interactions, the risk factors under investigation influenced activity of brain regions associated with response inhibition, suggesting they may add to problems with inhibiting behaviour.

Risk factors for comorbid oppositional defiant disorder in attention-deficit/hyperactivity disorder.

Oppositional defiant disorder (ODD) is highly prevalent in attention-deficit/hyperactivity disorder (ADHD). Individuals with both ADHD and ODD (ADHD + ODD) show a considerably worse prognosis compared with individuals with either ADHD or ODD. Therefore, identification of risk factors for ADHD + ODD is essential and may contribute to the development of (early) preventive interventions. Participants were matched for age, gender, and ADHD-subtype (diagnostic groups), and did not differ in IQ. Predictors included pre- and perinatal risk factors (pregnancy duration, birth weight, maternal smoking during pregnancy), transgenerational factors (parental ADHD; parental warmth and criticism in diagnostic groups), and postnatal risk factors (parental socioeconomic status [SES], adverse life events, deviant peer affiliation). Three models were assessed, investigating risk factors for ADHD-only versus controls (N = 86), ADHD + ODD versus controls (N = 86), and ADHD + ODD versus ADHD-only (N = 90). Adverse life events and parental ADHD were risk factors for both ADHD + ODD and ADHD-only, and more adverse life events were an even stronger risk factor for comorbid ODD compared with ADHD-only. For ADHD + ODD, but not ADHD-only, parental criticism, deviant peer affiliation, and parental SES acted as risk factors. Maternal smoking during pregnancy acted as minor risk factor for ADHD-only, while higher birth weight acted as minor risk factor for ADHD + ODD. No effects of age were present. Findings emphasise the importance of these factors in the development of comorbid ODD. The identified risk factors may prove to be essential in preventive interventions for comorbid ODD in ADHD, highlighting the need for parent-focused interventions to take these factors into account.

Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1.

The dopamine transporter gene, DAT1 (SLC6A3), has been studied extensively as a candidate gene for attention-deficit/hyperactivity disorder (ADHD). Different alleles of variable number of tandem repeats (VNTRs) in this gene have been associated with childhood ADHD (10/10 genotype and haplotype 10-6) and adult ADHD (haplotype 9-6). This suggests a differential association depending on age, and a role of DAT1 in modulating the ADHD phenotype over the lifespan. The DAT1 gene may mediate susceptibility to ADHD through effects on striatal volumes, where it is most highly expressed. In an attempt to clarify its mode of action, we examined the effect of three DAT1 alleles (10/10 genotype, and the haplotypes 10-6 and 9-6) on bilateral striatal volumes (nucleus accumbens, caudate nucleus, and putamen) derived from structural magnetic resonance imaging scans using automated tissue segmentation. Analyses were performed separately in three cohorts with cross-sectional MRI data, a childhood/adolescent sample (NeuroIMAGE, 301 patients with ADHD and 186 healthy participants) and two adult samples (IMpACT, 118 patients with ADHD and 111 healthy participants; BIG, 1718 healthy participants). Regression analyses revealed that in the IMpACT cohort, and not in the other cohorts, carriers of the DAT1 adult ADHD risk haplotype 9-6 had 5.9 % larger striatum volume relative to participants not carrying this haplotype. This effect varied by diagnostic status, with the risk haplotype affecting striatal volumes only in patients with ADHD. An explorative analysis in the cohorts combined (N = 2434) showed a significant gene-by-diagnosis-by-age interaction suggesting that carriership of the 9-6 haplotype predisposes to a slower age-related decay of striatal volume specific to the patient group. This study emphasizes the need of a lifespan approach in genetic studies of ADHD.

Aberrant local striatal functional connectivity in attention-deficit/hyperactivity disorder.

BACKGROUND: Task-based and resting-state functional Magnetic Resonance Imaging (fMRI) studies report attention-deficit/hyperactivity disorder (ADHD)-related alterations in brain regions implicated in cortico-striatal networks. We assessed whether ADHD is associated with changes in the brain's global cortico-striatal functional architecture, or whether ADHD-related alterations are limited to local, intrastriatal functional connections. METHODS: We included a cohort of adolescents with ADHD (N = 181) and healthy controls (N = 140) and assessed functional connectivity of nucleus accumbens, caudate nucleus, anterior putamen, and posterior putamen. To assess global cortico-striatal functional architecture we computed whole-brain functional connectivity by including all regions of interest in one multivariate analysis. We assessed local striatal functional connectivity using partial correlations between the time series of the striatal regions. RESULTS: Diagnostic status did not influence global cortico-striatal functional architecture. However, compared to controls, participants with ADHD exhibited significantly increased local functional connectivity between anterior and posterior putamen (p = .0003; ADHD: z = .30, controls: z = .24). Results were not affected by medication use or comorbid oppositional defiant disorder and conduct disorder. CONCLUSIONS: Our results do not support hypotheses that ADHD is associated with alterations in cortico-striatal networks, but suggest changes in local striatal functional connectivity. We interpret our findings as aberrant development of local functional connectivity of the putamen, potentially leading to decreased functional segregation between anterior and posterior putamen in ADHD.

Voxel-based morphometry analysis reveals frontal brain differences in participants with ADHD and their unaffected siblings.

BACKGROUND: Data on structural brain alterations in patients with attention-deficit/hyperactivity disorder (ADHD) have been inconsistent. Both ADHD and brain volumes have a strong genetic loading, but whether brain alterations in patients with ADHD are familial has been underexplored. We aimed to detect structural brain alterations in adolescents and young adults with ADHD compared with healthy controls. We examined whether these alterations were also found in their unaffected siblings, using a uniquely large sample. METHODS: We performed voxel-based morphometry analyses on MRI scans of patients with ADHD, their unaffected siblings and typically developing controls. We identified brain areas that differed between participants with ADHD and controls and investigated whether these areas were different in unaffected siblings. Influences of medication use, age, sex and IQ were considered. RESULTS: Our sample included 307 patients with ADHD, 169 unaffected siblings and 196 typically developing controls (mean age 17.2 [range 8-30] yr). Compared with controls, participants with ADHD had significantly smaller grey matter volume in 5 clusters located in the precentral gyrus, medial and orbitofrontal cortex, and (para)cingulate cortices. Unaffected siblings showed intermediate volumes significantly different from controls in 4 of these clusters (all except the precentral gyrus). Medication use, age, sex and IQ did not have an undue influence on the results. LIMITATIONS: Our sample was heterogeneous, most participants with ADHD were taking medication, and the comparison was cross-sectional. CONCLUSION: Brain areas involved in decision making, motivation, cognitive control and motor functioning were smaller in participants with ADHD than in controls. Investigation of unaffected siblings indicated familiality of 4 of the structural brain differences, supporting their potential in molecular genetic analyses in ADHD research.

The influence of comorbid oppositional defiant disorder on white matter microstructure in attention-deficit/hyperactivity disorder.

Attention-deficit/hyperactivity disorder (ADHD) and oppositional defiant disorder (ODD) are highly comorbid disorders. ADHD has been associated with altered white matter (WM) microstructure, though the literature is inconsistent, which may be due to differences in the in- or exclusion of participants with comorbid ODD. WM abnormalities in ODD are still poorly understood, and it is unclear whether comorbid ODD in ADHD may have confounded the current ADHD literature. Diffusion Tensor Imaging (DTI) was used to compare fractional anisotropy (FA) and mean diffusivity (MD) between ADHD patients with (n = 42) and without (n = 117) comorbid ODD. All participants were between 8-25 years and groups did not differ in mean age or gender. Follow-up analyses were conducted to examine the role of antisocial behaviour (conduct problems) on FA and MD values in both groups. Comorbid ODD in ADHD was associated with lower FA in left frontotemporal WM, which appeared independent of ADHD symptoms. FA was negatively associated with antisocial behaviour in ADHD + ODD, but not in ADHD-only. Comorbid ODD is associated with WM abnormalities in individuals with ADHD, which appears to be independent of ADHD symptoms. Altered WM microstructure in comorbid ODD may play a role in inconsistencies in the current DTI literature in ADHD. Altered development of these tracts may contribute to social-emotional and cognitive problems in children with oppositional and antisocial behaviour.

A 6-year follow-up of a large European cohort of children with attention-deficit/hyperactivity disorder-combined subtype: outcomes in late adolescence and young adulthood.

There are very few studies on the long-term outcome of children and adolescents with ADHD-combined type in Europe. The objective of the present study is to assess the 6-year outcome (including pharmacological treatment) of a large cohort of participants with ADHD-combined type (N = 347, mean age 11.4 years) in late adolescence and early adulthood. At study entry and follow-up (mean age 17.4 years), participants were comprehensively assessed on ADHD and comorbid disorders by structured psychiatric interviews and multi-informant questionnaires. Overall functioning was assessed by the Children's Global Assessment Scale. The retention rate was 75.6 %. The majority of participants (86.5 %) persisted in a DSM-5 ADHD diagnosis, 8.4 % had a subthreshold diagnosis, and 5.1 % remitted from the disorder at follow-up. Comorbidities decreased strongly; oppositional defiant disorder: 58 > 31 %, conduct disorder: 19 > 7 %. At follow-up, mood- and anxiety disorders were virtually non-existent following strict criteria (1-3 %). Percentage of children having had pharmacological treatment at any time increased from 79 to 91 %. On the Children's Global Assessment Scale, 48.5 % of participants were still functionally impaired at follow-up. Parental ADHD, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline positively predicted current ADHD symptom severity (R (2) = 20.9 %). Younger baseline age, higher ADHD symptom severity at baseline and higher parent-reported impairment at baseline were positively associated with poorer overall functioning (R (2) = 17.8 %). Pharmacological treatment had no (beneficial) impact on either ADHD symptom severity or overall functioning. Results confirm that ADHD is largely persistent into late adolescence with severity and family history for the disorder as important risk factors.

Smoking and the developing brain: altered white matter microstructure in attention-deficit/hyperactivity disorder and healthy controls.

Brain white matter (WM) tracts, playing a vital role in the communication between brain regions, undergo important maturational changes during adolescence and young adulthood, a critical period for the development of nicotine dependence. Attention-deficit/hyperactivity disorder (ADHD) is associated with increased smoking and widespread WM abnormalities, suggesting that the developing ADHD brain might be especially vulnerable to effects of smoking. This study aims to investigate the effect of smoking on (WM) microstructure in adolescents and young adults with and without ADHD. Diffusion tensor imaging was performed in an extensively phenotyped sample of nonsmokers (n = 95, 50.5% ADHD), irregular smokers (n = 41, 58.5% ADHD), and regular smokers (n = 50, 82.5% ADHD), aged 14-24 years. A whole-brain voxelwise approach investigated associations of smoking, ADHD and their interaction, with WM microstructure as measured by fractional anisotropy (FA) and mean diffusivity (MD). Widespread alterations in FA and MD were found for regular smokers compared to irregular and nonsmokers, mainly located in the corpus callosum and WM tracts surrounding the basal ganglia. Several regions overlapped with regions of altered FA for ADHD versus controls, albeit in different directions. Irregular and nonsmokers did not differ, and ADHD and smoking did not interact. Results implicate that smoking and ADHD have independent effects on WM microstructure, and possibly do not share underlying mechanisms. Two mechanisms may play a role in the current results. First, smoking may cause alterations in WM microstructure in the maturing brain. Second, pre-existing WM microstructure differences possibly reflect a risk factor for development of a smoking addiction.

White matter microstructure and developmental improvement of hyperactive/impulsive symptoms in attention-deficit/hyperactivity disorder.

BACKGROUND: A developmental improvement of symptoms in attention-deficit/hyperactivity disorder (ADHD) is frequently reported, but the underlying neurobiological substrate has not been identified. The aim of this study was to determine whether white matter microstructure is related to developmental improvement of ADHD symptoms. METHODS: A cross-sectional magnetic resonance imaging (MRI) analysis was embedded in a prospective follow-up of an adolescent cohort of ADHD and control subjects (NeuroIMAGE). Mean age at baseline was 11.9 years, mean interval of follow-up was 5.9 years. About 75.3% of the original cohort was retained successfully. Data of 101 participants with ADHD combined type at baseline and 40 healthy controls were analysed. ADHD symptoms were measured with semistructured, investigator-based interviews and Conners' questionnaires, on the basis of DSM-IV criteria. Fractional anisotropy (FA) and mean diffusivity (MD) indices of white matter microstructure were measured using whole brain diffusion tensor imaging at follow-up only. In a dimensional analysis FA and MD were related to change in ADHD symptoms. To link this analysis to DSM-IV diagnoses, a post hoc categorical group analysis was conducted comparing participants with persistent (n = 59) versus remittent (n = 42) ADHD and controls. RESULTS: Over time, participants with ADHD showed improvement mainly in hyperactive/impulsive symptoms. This improvement was associated with lower FA and higher MD values in the left corticospinal tract at follow-up. Findings of the dimensional and the categorical analysis strongly converged. Changes in inattentive symptoms over time were minimal and not related to white matter microstructure. CONCLUSIONS: The corticospinal tract is important in the control of voluntary movements, suggesting the importance of the motor system in the persistence of hyperactive/impulsive symptoms.

Differential susceptibility to maternal expressed emotion in children with ADHD and their siblings? Investigating plasticity genes, prosocial and antisocial behaviour.

The differential susceptibility theory states that children differ in their susceptibility towards environmental experiences, partially due to plasticity genes. Individuals carrying specific variants in such genes will be more disadvantaged in negative but, conversely, more advantaged in positive environments. Understanding gene-environment interactions may help unravel the causal mechanisms involved in multifactorial psychiatric disorders such as Attention-Deficit/Hyperactivity Disorder (ADHD). The differential susceptibility theory was examined by investigating the presence of interaction effects between maternal expressed emotion (EE; warmth and criticism) and the solitary and combined effects of plasticity genes (DAT1, DRD4, 5-HTT) on prosocial and antisocial behaviour (measured with parent- and self-reports) in children with ADHD and their siblings (N = 366, M = 17.11 years, 74.9% male). Maternal warmth was positively associated with prosocial behaviour and negatively with antisocial behaviour, while maternal criticism was positively associated with antisocial behaviour and negatively with prosocial behaviour. No evidence of differential susceptibility was found. The current study found no evidence for differential susceptibility based on the selected plasticity genes, in spite of strong EE-behaviour associations. It is likely that additional factors play a role in the complex relationship between genes, environment and behaviour.

The NeuroIMAGE study: a prospective phenotypic, cognitive, genetic and MRI study in children with attention-deficit/hyperactivity disorder. Design and descriptives.

Attention-deficit/hyperactivity disorder (ADHD) is a persistent neuropsychiatric disorder which is associated with impairments on a variety of cognitive measures and abnormalities in structural and functional brain measures. Genetic factors are thought to play an important role in the etiology of ADHD. The NeuroIMAGE study is a follow-up of the Dutch part of the International Multicenter ADHD Genetics (IMAGE) project. It is a multi-site prospective cohort study designed to investigate the course of ADHD, its genetic and environmental determinants, its cognitive and neurobiological underpinnings, and its consequences in adolescence and adulthood. From the original 365 ADHD families and 148 control (CON) IMAGE families, consisting of 506 participants with an ADHD diagnosis, 350 unaffected siblings, and 283 healthy controls, 79 % participated in the NeuroIMAGE follow-up study. Combined with newly recruited participants the NeuroIMAGE study comprehends an assessment of 1,069 children (751 from ADHD families; 318 from CON families) and 848 parents (582 from ADHD families; 266 from CON families). For most families, data for more than one child (82 %) and both parents (82 %) were available. Collected data include a diagnostic interview, behavioural questionnaires, cognitive measures, structural and functional neuroimaging, and genome-wide genetic information. The NeuroIMAGE dataset allows examining the course of ADHD over adolescence into young adulthood, identifying phenotypic, cognitive, and neural mechanisms associated with the persistence versus remission of ADHD, and studying their genetic and environmental underpinnings. The inclusion of siblings of ADHD probands and controls allows modelling of shared familial influences on the ADHD phenotype.

The role of age in association analyses of ADHD and related neurocognitive functioning: A proof of concept for dopaminergic and serotonergic genes.

Elucidating genetic mechanisms involved in Attention-Deficit/Hyperactivity Disorder (ADHD) has been challenging. Relatively unexplored is the fact that genetic mechanisms can differ with age. The current study explored the association between dopaminergic and serotonergic genes, ADHD symptoms, and neurocognitive functioning in relation to age. Associations of three genetic ADHD risk factors, DAT1, DRD4, and 5-HTT with symptoms and six neurocognitive measures were explored in two samples of the NeuroIMAGE study: 756 children, adolescents, and young adults with ADHD, their siblings, and controls (M age 17 years, SD 3.2), and 393 parents with and without ADHD (M age 48 years, SD 4.8). Association analyses were performed in both samples, and effects were compared to address dichotomous age effects. Gene*age interactions were examined to address continuous age effects. Moderating effects of age were found for DRD4-7R carriership and ADHD symptoms in the adult group only; in the adolescents the 5-HTT LL genotype was differentially associated with inhibition and with motor timing at different ages, and to inhibition in adults; DAT1 10-6 haplotype carriership showed differential working memory performance depending on age. None of our effects survived correction for multiple comparisons. Our results are preliminary, but may point to differential genotype-phenotype associations at different ages. This can be seen as a proof of concept for the importance of age in dopaminergic and serotonergic genetic association analyses. Our findings are consistent with the idea that genetic and neurocognitive mechanisms underlying ADHD may change throughout life. © 2015 Wiley Periodicals, Inc.

The eye as a window to the listening brain: neural correlates of pupil size as a measure of cognitive listening load.

An important aspect of hearing is the degree to which listeners have to deploy effort to understand speech. One promising measure of listening effort is task-evoked pupil dilation. Here, we use functional magnetic resonance imaging (fMRI) to identify the neural correlates of pupil dilation during comprehension of degraded spoken sentences in 17 normal-hearing listeners. Subjects listened to sentences degraded in three different ways: the target female speech was masked by fluctuating noise, by speech from a single male speaker, or the target speech was noise-vocoded. The degree of degradation was individually adapted such that 50% or 84% of the sentences were intelligible. Control conditions included clear speech in quiet, and silent trials. The peak pupil dilation was larger for the 50% compared to the 84% intelligibility condition, and largest for speech masked by the single-talker masker, followed by speech masked by fluctuating noise, and smallest for noise-vocoded speech. Activation in the bilateral superior temporal gyrus (STG) showed the same pattern, with most extensive activation for speech masked by the single-talker masker. Larger peak pupil dilation was associated with more activation in the bilateral STG, bilateral ventral and dorsal anterior cingulate cortex and several frontal brain areas. A subset of the temporal region sensitive to pupil dilation was also sensitive to speech intelligibility and degradation type. These results show that pupil dilation during speech perception in challenging conditions reflects both auditory and cognitive processes that are recruited to cope with degraded speech and the need to segregate target speech from interfering sounds.

A crucial role for white matter alterations in interference control problems of very preterm children.

BACKGROUND: Attention problems are among the most prominent behavioral deficits reported in very preterm children (below 32 wk of gestation) at school age. In this study, we aimed to elucidate the brain abnormalities underlying attention problems in very preterm children by investigating the role of abnormalities in white and gray brain matter during interference control, using functional magnetic resonance imaging (fMRI)-guided probabilistic diffusion tensor tractography. METHODS: Twenty-nine very preterm children (mean (SD) age: 8.6 (0.3) y), and 47 term controls (mean (SD) age: 8.7 (0.5) y), performed a fMRI version of the Eriksen Flanker task measuring interference control. RESULTS: Very preterm children showed slower reaction times than term controls when interfering stimuli were presented, indicating poorer interference control. Very preterm children and term controls did not differ in mean activation of the cortical regions involved in interference control. However, impaired fractional anisotropy (FA) was found in very preterm children in specifically those fiber tracts that innervate the cortical regions involved in interference control. Lower FA was related to poorer interference control in very preterm children. CONCLUSION: White matter alterations have a crucial role in the interference control problems of very preterm children at school age.

The serotonin transporter gene polymorphism 5-HTTLPR moderates the effects of stress on attention-deficit/hyperactivity disorder.

INTRODUCTION: The role of the serotonin transporter gene polymorphism 5-HTTLPR in attention-deficit/hyperactivity disorder (ADHD) is unclear. Heterogeneity of findings may be explained by gene-environment interactions (GxE), as it has been suggested that S-allele carriers are more reactive to psychosocial stress than L-allele homozygotes. This study aimed to investigate whether 5-HTTLPR genotype moderates the effects of stress on ADHD in a multisite prospective ADHD cohort study. METHODS: 5-HTTLPR genotype, as well as the number of stressful life events in the past 5 years and ongoing long-term difficulties, was determined in 671 adolescents and young adults with ADHD, their siblings, and healthy controls (57.4% male, average age 17.3 years). Linear mixed models, accounting for family relatedness, were applied to investigate the effects of genotype, experienced stress, and their interaction on ADHD severity at time point T2, while controlling for ADHD severity at T1 (mean follow-up time 5.9 years) and for comorbid internalizing problems at T2. RESULTS: The interaction between genotype and stress significantly predicted ADHD severity at T2 (p = .006), which was driven by the effect on hyperactivity-impulsivity (p = .004). Probing of the interaction effect made clear that S-allele carriers had a significantly more positive correlation between stress and ADHD severity than L-allele homozygotes. CONCLUSION: The results show that the interaction between 5-HTTLPR and stress is a mechanism involved particularly in the hyperactivity/impulsivity dimension of ADHD, and that this is independent of comorbid internalizing problems. Further research into the neurobiological mechanisms underlying this interaction effect is warranted.