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1.  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. 75.3% of the original cohort was retained successfully. Data of 101 participants with ADHD combined type at baseline and 40 healthy controls was analysed. ADHD symptoms were measured with semi-structured, 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.
doi:10.1111/jcpp.12379
PMCID: PMC4499023  PMID: 25581343
ADHD; hyperactivity/impulsivity; white matter; DTI; recovery; development
2.  Do Elite and Amateur Soccer Players Outperform Non-Athletes on Neurocognitive Functioning? A Study Among 8-12 Year Old Children 
PLoS ONE  2016;11(12):e0165741.
Aim
Research suggested a positive association between physical fitness and neurocognitive functioning in children. Aim of the present study is to investigate possible dose-response relationships between diverse daily physical activities and a broad range of neurocognitive functions in preadolescent children. Furthermore, the relationship between several sedentary behaviours, including TV-watching, gaming and computer time, and neurocognitive functioning will be investigated in this group of children.
Methods
A total of 168 preadolescent boys, aged 8 to 12 years, were recruited from various locations, including primary schools, an amateur soccer club, and a professional soccer club, to increase variability in the amount of participation in sports. All children performed neurocognitive tasks measuring inhibition, short term memory, working memory, attention and information processing speed. Regression analyses examined the predictive power of a broad range of physical activities, including sports, active transport to school, physical education (PE), outdoor play, and sedentary behaviour such as TV-watching and gaming, for neurocognitive functioning.
Results
Time spent in sports significantly accounted for the variance in inhibition, short term memory, working memory and lapses of attention, where more time spent in sports was associated with better performance. Outdoor play was also positively associated with working memory. In contrast, time spent on the computer was negatively associated with inhibition.
Conclusions
Results of the current study suggest a positive relationship between participation in sports and several important neurocognitive functions. Interventions are recommended to increase sports participation and to reduce sedentary behaviour in preadolescent children.
doi:10.1371/journal.pone.0165741
PMCID: PMC5131928  PMID: 27906965
3.  Decreased Left Caudate Volume Is Associated with Increased Severity of Autistic-Like Symptoms in a Cohort of ADHD Patients and Their Unaffected Siblings 
PLoS ONE  2016;11(11):e0165620.
Autism spectrum disorder (ASD) symptoms frequently occur in individuals with attention-deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural brain correlates, knowledge of the structural brain profile of individuals with ADHD with raised ASD symptoms is limited. The presence of ASD-like symptoms was measured by the Children's Social Behavior Questionnaire (CSBQ) in a sample of typically developing controls (n = 154), participants with ADHD (n = 239), and their unaffected siblings (n = 144) between the ages of 8 and 29. Structural magnetic resonance imaging (MRI) correlates of ASD ratings were analysed by studying the relationship between ASD ratings and grey matter volumes using mixed effects models which controlled for ADHD symptom count and total brain volume. ASD ratings were significantly elevated in participants with ADHD relative to controls and unaffected siblings. For the entire group (participants with ADHD, unaffected siblings and TD controls), mixed effect models revealed that the left caudate nucleus volume was negatively correlated with ASD ratings (t = 2.83; P = 0.005). The current findings are consistent with the role of the caudate nucleus in executive function, including the selection of goals based on the evaluation of action outcomes and the use of social reward to update reward representations. There is a specific volumetric profile associated with subclinical ASD-like symptoms in participants with ADHD, unaffected siblings and controls with the caudate nucleus and globus pallidus being of critical importance in predicting the level of ASD-like symptoms in all three groups.
doi:10.1371/journal.pone.0165620
PMCID: PMC5091763  PMID: 27806078
4.  Functional connectivity in cortico-subcortical brain networks underlying reward processing in attention-deficit/hyperactivity disorder 
NeuroImage : Clinical  2016;12:796-805.
Background
Many patients with attention-deficit/hyperactivity disorder (ADHD) display aberrant reward-related behavior. Task-based fMRI studies have related atypical reward processing in ADHD to altered BOLD activity in regions underlying reward processing such as ventral striatum and orbitofrontal cortex. However, it remains unclear whether the observed effects are region-specific or related to changes in functional connectivity of networks supporting reward processing. Here we use resting-state fMRI to comprehensively delineate the functional connectivity architecture underlying aberrant reward processing in ADHD.
Methods
We assessed resting-state functional connectivity of four networks that support reward processing. These networks showed high spatial overlap with the default mode, fronto-parietal, lateral visual, and salience networks, yet only activity within the salience network was effectively sensitive to reward value. We parcelled these networks into their functional cortical and subcortical subregions and obtained functional connectivity matrices by computing Pearson correlations between the regional time series. We compared functional connectivity within each of the four networks between participants with ADHD and controls, and related functional connectivity to dimensional ADHD symptom scores across all participants (N = 444; age range: 8.5–30.5; mean age: 17.7).
Results
We did not observe significant ADHD-related alterations in functional connectivity of the salience network, which included key reward regions. Instead, levels of inattention symptoms modulated functional connectivity of the default-mode and fronto-parietal networks, which supported general task processing.
Conclusions
The present study does not corroborate previous childhood evidence for functional connectivity alterations between key reward processing regions in adolescents and young adults with ADHD. Our findings could point to developmental normalization or indicate that reward-processing deficits result from functional connectivity alterations in general task-related networks.
Highlights
•We delineated functional subregions in major networks that support reward processing.•ADHD-related effects on functional connectivity between regions were examined.•ADHD did not affect functional connectivity patterns of key reward regions.•ADHD affected functional connectivity within default-mode & fronto-parietal networks.•Atypical reward behavior in ADHD might result from changes in general task networks.
doi:10.1016/j.nicl.2016.10.006
PMCID: PMC5081416  PMID: 27818941
ADHD; Reward; Resting-state fMRI; Functional parcellation; Functional connectivity; Default mode network; Fronto-parietal network
5.  Quantifying patterns of brain activity: Distinguishing unaffected siblings from participants with ADHD and healthy individuals 
NeuroImage : Clinical  2016;12:227-233.
Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent and heritable psychiatric disorders. While previous studies have focussed on mapping focal or connectivity differences at the group level, the present study employed pattern recognition to quantify group separation between unaffected siblings, participants with ADHD, and healthy controls on the basis of spatially distributed brain activations. This was achieved using an fMRI-adapted version of the Stop-Signal Task in a sample of 103 unaffected siblings, 184 participants with ADHD, and 128 healthy controls. We used activation maps derived from three task regressors as features in our analyses employing a Gaussian process classifier. We showed that unaffected siblings could be distinguished from participants with ADHD (area under the receiver operating characteristic curve (AUC) = 0.65, p = 0.002, 95% Modified Wald CI: 0.59–0.71 AUC) and healthy controls (AUC = 0.59, p = 0.030, 95% Modified Wald CI: 0.52–0.66 AUC), although the latter did not survive correction for multiple comparisons. Further, participants with ADHD could be distinguished from healthy controls (AUC = 0.64, p = 0.001, 95% Modified Wald CI: 0.58–0.70 AUC). Altogether the present results characterise a pattern of frontolateral, superior temporal and inferior parietal expansion that is associated with risk for ADHD. Unaffected siblings show differences primarily in frontolateral regions. This provides evidence for a neural profile shared between participants with ADHD and their healthy siblings.
Highlights
•Multivariate profile of risk shared between ADHD patients and unaffected siblings•Pattern of risk in frontolateral, superior temporal and inferior parietal regions•Benchmark estimate of classification performance in heterogeneous samples
doi:10.1016/j.nicl.2016.06.020
PMCID: PMC4950173  PMID: 27489770
Pattern recognition; Gaussian process classification; fMRI; Response inhibition; Attention-deficit/hyperactivity disorder; Unaffected siblings
6.  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.
doi:10.1503/jpn.140377
PMCID: PMC4915936  PMID: 26679925
7.  Developmentally Sensitive Interaction Effects of Genes and the Social Environment on Total and Subcortical Brain Volumes 
PLoS ONE  2016;11(5):e0155755.
Smaller total brain and subcortical volumes have been linked to psychopathology including attention-deficit/hyperactivity disorder (ADHD). Identifying mechanisms underlying these alterations, therefore, is of great importance. We investigated the role of gene-environment interactions (GxE) in interindividual variability of total gray matter (GM), caudate, and putamen volumes. Brain volumes were derived from structural magnetic resonance imaging scans in participants with (N = 312) and without ADHD (N = 437) from N = 402 families (age M = 17.00, SD = 3.60). GxE effects between DAT1, 5-HTT, and DRD4 and social environments (maternal expressed warmth and criticism; positive and deviant peer affiliation) as well as the possible moderating effect of age were examined using linear mixed modeling. We also tested whether findings depended on ADHD severity. Deviant peer affiliation was associated with lower caudate volume. Participants with low deviant peer affiliations had larger total GM volumes with increasing age. Likewise, developmentally sensitive GxE effects were found on total GM and putamen volume. For total GM, differential age effects were found for DAT1 9-repeat and HTTLPR L/L genotypes, depending on the amount of positive peer affiliation. For putamen volume, DRD4 7-repeat carriers and DAT1 10/10 homozygotes showed opposite age relations depending on positive peer affiliation and maternal criticism, respectively. All results were independent of ADHD severity. The presence of differential age-dependent GxE effects might explain the diverse and sometimes opposing results of environmental and genetic effects on brain volumes observed so far.
doi:10.1371/journal.pone.0155755
PMCID: PMC4878752  PMID: 27218681
8.  Increased Neural Responses to Reward in Adolescents and Young Adults With Attention-Deficit/Hyperactivity Disorder and Their Unaffected Siblings 
Objective
Attention-deficit/hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder associated with abnormal reward processing. Limited and inconsistent data exist about the neural mechanisms underlying this abnormality. Furthermore, it is unknown whether reward processing is abnormal in unaffected siblings of participants with ADHD.
Method
We used event-related functional magnetic resonance imaging (fMRI) to investigate brain responses during reward anticipation and receipt with an adapted monetary incentive delay task in a large sample of adolescents and young adults with ADHD (n=150), their unaffected siblings (n=92), and control participants (n=108), all of the same age.
Results
Participants with ADHD showed, relative to control participants, increased responses in the anterior cingulate, anterior frontal cortex, and cerebellum during reward anticipation, and in the orbitofrontal, occipital cortex, and ventral striatum during reward receipt. Responses of unaffected siblings were increased in these regions as well, except for the cerebellum during anticipation and the orbitofrontal cortex during receipt.
Conclusion
ADHD in adolescents and young adults is associated with enhanced neural responses in frontostriatal circuitry to anticipation and receipt of reward. The findings support models emphasizing aberrant reward processing in ADHD and suggest that processing of reward is subject to familial influences. Future studies using standard monetary incentive delay task parameters have to replicate our findings.
doi:10.1016/j.jaac.2015.02.012
PMCID: PMC4417499  PMID: 25901776
ADHD; reward processing; cognitive control; familiality; nucleus accumbens
9.  Integrated analysis of gray and white matter alterations in attention-deficit/hyperactivity disorder 
NeuroImage : Clinical  2016;11:357-367.
Background
Magnetic resonance imaging (MRI) is able to provide detailed insights into the structural organization of the brain, e.g., by means of mapping brain anatomy and white matter microstructure. Understanding interrelations between MRI modalities, rather than mapping modalities in isolation, will contribute to unraveling the complex neural mechanisms associated with neuropsychiatric disorders as deficits detected across modalities suggest common underlying mechanisms. Here, we conduct a multimodal analysis of structural MRI modalities in the context of attention-deficit/hyperactivity disorder (ADHD).
Methods
Gray matter volume, cortical thickness, surface areal expansion estimates, and white matter diffusion indices of 129 participants with ADHD and 204 participants without ADHD were entered into a linked independent component analysis. This data-driven analysis decomposes the data into multimodal independent components reflecting common inter-subject variation across imaging modalities.
Results
ADHD severity was related to two multimodal components. The first component revealed smaller prefrontal volumes in participants with more symptoms, co-occurring with abnormal white matter indices in prefrontal cortex. The second component demonstrated decreased orbitofrontal volume as well as abnormalities in insula, occipital, and somato-sensory areas in participants with more ADHD symptoms.
Conclusions
Our results replicate and extend previous unimodal structural MRI findings by demonstrating that prefrontal, parietal, and occipital areas, as well as fronto-striatal and fronto-limbic systems are implicated in ADHD. By including multiple modalities, sensitivity for between-participant effects is increased, as shared variance across modalities is modeled. The convergence of modality-specific findings in our results suggests that different aspects of brain structure share underlying pathophysiology and brings us closer to a biological characterization of ADHD.
Highlights
•We use a multimodal approach (Linked ICA) to investigate changes in brain structure related to ADHD.•Linked ICA decomposes multimodal data into networks and links the modalities by assigning a shared-subject course.•Both white and gray matter show spatially consistent abnormalities.•Same subjects are driving the patterns present in different modalities.•We replicate previous unimodal findings.
doi:10.1016/j.nicl.2016.03.005
PMCID: PMC4893015  PMID: 27298764
ADHD; Structural MRI; Multimodal analysis; Gray matter; White matter
10.  No Tryptophan, Tyrosine and Phenylalanine Abnormalities in Children with Attention-Deficit/Hyperactivity Disorder 
PLoS ONE  2016;11(3):e0151100.
Background
The aim of the current study was to explore the role of aromatic amino acids (AAAs) in blood in relation to attention-deficit/hyperactivity disorder (ADHD). Given their impact on the synthesis of serotonin and dopamine, decreased concentrations of the AAAs tryptophan, tyrosine and phenylalanine in blood may contribute to the expression of ADHD symptoms. Decreased AAA blood concentrations, in turn, may be related to lowered dietary protein intake or to abnormal AAA catabolism, as evidenced by increased urinary AAA concentrations.
Methods
Eighty-three children with ADHD (75% males) and 72 typically developing (TD) children (51% males), aged 6 to 13 years, participated in the study. AAA concentrations were assessed in blood spots and an 18-hour urinary sample. A nutritional diary was filled out by parents to calculate dietary protein intake. Parent and teacher questionnaires assessed symptoms of ADHD, oppositional defiant disorder, conduct disorder, and autism spectrum disorder.
Results
Children with ADHD showed normal AAA concentrations in blood spots and urine, as well as normal protein intake compared to controls. No associations between AAA concentrations and symptoms of ADHD or comorbid psychiatric disorders were found.
Conclusions
This study is the first to explore AAA metabolism in children with ADHD using a well-defined and relatively large sample. We found that AAA deficiencies are not related to ADHD. The results do not support treatment with AAA supplements in children with ADHD. Future studies regarding the cause of serotonin and dopamine alterations in ADHD should focus on other explanations, such as effects of altered transport of AAAs.
doi:10.1371/journal.pone.0151100
PMCID: PMC4777504  PMID: 26938936
11.  Enlarged striatal volume in adults with ADHD carrying the 9-6 haplotype of the dopamine transporter gene DAT1 
Journal of Neural Transmission  2016;123:905-915.
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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00702-016-1521-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00702-016-1521-x
PMCID: PMC4969340  PMID: 26935821
ADHD; DAT1 gene; Striatum; Volumetry
12.  A Systematic Review and Meta-analysis of Neuroimaging in Oppositional Defiant Disorder (ODD) and Conduct Disorder (CD) Taking Attention-Deficit Hyperactivity Disorder (ADHD) Into Account 
Neuropsychology Review  2016;26:44-72.
Oppositional defiant disorder (ODD) and conduct disorder (CD) are common behavioural disorders in childhood and adolescence and are associated with brain abnormalities. This systematic review and meta-analysis investigates structural (sMRI) and functional MRI (fMRI) findings in individuals with ODD/CD with and without attention-deficit hyperactivity disorder (ADHD). Online databases were searched for controlled studies, resulting in 12 sMRI and 17 fMRI studies. In line with current models on ODD/CD, studies were classified in hot and cool executive functioning (EF). Both the meta-analytic and narrative reviews showed evidence of smaller brain structures and lower brain activity in individuals with ODD/CD in mainly hot EF-related areas: bilateral amygdala, bilateral insula, right striatum, left medial/superior frontal gyrus, and left precuneus. Evidence was present in both structural and functional studies, and irrespective of the presence of ADHD comorbidity. There is strong evidence that abnormalities in the amygdala are specific for ODD/CD as compared to ADHD, and correlational studies further support the association between abnormalities in the amygdala and ODD/CD symptoms. Besides the left precuneus, there was no evidence for abnormalities in typical cool EF related structures, such as the cerebellum and dorsolateral prefrontal cortex. Resulting areas are associated with emotion-processing, error-monitoring, problem-solving and self-control; areas associated with neurocognitive and behavioural deficits implicated in ODD/CD. Our findings confirm the involvement of hot, and to a smaller extent cool, EF associated brain areas in ODD/CD, and support an integrated model for ODD/CD (e.g. Blair, Development and Psychopathology, 17(3), 865-891, 2005).
doi:10.1007/s11065-015-9315-8
PMCID: PMC4762933  PMID: 26846227
ODD; CD; ADHD; Structural MRI; Functional MRI; ALE meta-analysis
13.  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 (R2 = 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 (R2 = 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.
Electronic supplementary material
The online version of this article (doi:10.1007/s00787-016-0820-y) contains supplementary material, which is available to authorized users.
doi:10.1007/s00787-016-0820-y
PMCID: PMC4990613  PMID: 26837866
ADHD; Persistence; Symptom severity; Overall functioning; Prediction; Follow-up; Treatment
14.  Differential Susceptibility to Maternal Expressed Emotion in Children with ADHD and their Siblings? Investigating Plasticity Genes, Prosocial and Antisocial Behaviour 
Background
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 advantageous 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).
Methods
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).
Results
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.
Conclusions
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.
doi:10.1007/s00787-014-0567-2
PMCID: PMC4266623  PMID: 24929324
Maternal expressed emotion; antisocial behaviour; prosocial behaviour; GxE interaction
15.  Cognitive Functions in Elite and Sub-Elite Youth Soccer Players Aged 13 to 17 Years 
PLoS ONE  2015;10(12):e0144580.
Soccer players are required to anticipate and react continuously in a changing, relatively unpredictable situation in the field. Cognitive functions might be important to be successful in soccer. The current study investigated the relationship between cognitive functions and performance level in elite and sub-elite youth soccer players aged 13–17 years. A total of 47 elite youth soccer players (mean age 15.5 years, SD = 0.9) and 41 sub-elite youth soccer players (mean age 15.2 years, SD = 1.2) performed tasks for “higher-level” cognitive functions measuring working memory (i.e., Visual Memory Span), inhibitory control (i.e., Stop-Signal Task), cognitive flexibility (i.e., Trail Making Test), and metacognition (i.e., Delis-Kaplan Executive Function System Design Fluency Test). “Lower-level” cognitive processes, i.e., reaction time and visuo-perceptual abilities, were also measured with the previous tasks. ANOVA’s showed that elite players outscored sub-elite players at the “higher-level” cognitive tasks only, especially on metacognition (p < .05). Using stepwise discriminant analysis, 62.5% of subjects was correctly assigned to one of the groups based on their metacognition, inhibitory control and cognitive flexibility performance. Controlling for training hours and academic level, MANCOVA’s showed differences in favor of the elite youth soccer players on inhibitory control (p = .001), and cognitive flexibility (p = .042), but not on metacognition (p = .27). No differences were found concerning working memory nor the “lower-level” cognitive processes (p > .05). In conclusion, elite youth soccer players have better inhibitory control, cognitive flexibility, and especially metacognition than their sub-elite counterparts. However, when training hours are taken into account, differences between elite and sub-elite youth soccer players remain apparent on inhibitory control and cognitive flexibility in contrast to metacognition. This highlights the need for longitudinal studies to further investigate the importance of “higher-level” cognitive functions for talent identification, talent development and performance in soccer.
doi:10.1371/journal.pone.0144580
PMCID: PMC4691195  PMID: 26657073
16.  Impaired Visual Integration in Children with Traumatic Brain Injury: An Observational Study 
PLoS ONE  2015;10(12):e0144395.
Background
Axonal injury after traumatic brain injury (TBI) may cause impaired sensory integration. We aim to determine the effects of childhood TBI on visual integration in relation to general neurocognitive functioning.
Methods
We compared children aged 6–13 diagnosed with TBI (n = 103; M = 1.7 years post-injury) to children with traumatic control (TC) injury (n = 44). Three TBI severity groups were distinguished: mild TBI without risk factors for complicated TBI (mildRF- TBI, n = 22), mild TBI with ≥1 risk factor (mildRF+ TBI, n = 46) or moderate/severe TBI (n = 35). An experimental paradigm measured speed and accuracy of goal-directed behavior depending on: (1) visual identification; (2) visual localization; or (3) both, measuring visual integration. Group-differences on reaction time (RT) or accuracy were tracked down to task strategy, visual processing efficiency and extra-decisional processes (e.g. response execution) using diffusion model analysis. General neurocognitive functioning was measured by a Wechsler Intelligence Scale short form.
Results
The TBI group had poorer accuracy of visual identification and visual integration than the TC group (Ps ≤ .03; ds ≤ -0.40). Analyses differentiating TBI severity revealed that visual identification accuracy was impaired in the moderate/severe TBI group (P = .05, d = -0.50) and that visual integration accuracy was impaired in the mildRF+ TBI group and moderate/severe TBI group (Ps < .02, ds ≤ -0.56). Diffusion model analyses tracked impaired visual integration accuracy down to lower visual integration efficiency in the mildRF+ TBI group and moderate/severe TBI group (Ps < .001, ds ≤ -0.73). Importantly, intelligence impairments observed in the TBI group (P = .009, d = -0.48) were statistically explained by visual integration efficiency (P = .002).
Conclusions
Children with mildRF+ TBI or moderate/severe TBI have impaired visual integration efficiency, which may contribute to poorer general neurocognitive functioning.
doi:10.1371/journal.pone.0144395
PMCID: PMC4670090  PMID: 26637182
17.  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 effects of stress on ADHD in a multi-site prospective ADHD cohort study.
Methods
5-HTTLPR genotype, as well as the number of stressful life events in the past five years and ongoing long-term difficulties, were 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.
doi:10.1111/jcpp.12240
PMCID: PMC4218913  PMID: 24797917
ADHD; gene-environment interaction (GxE); stress; serotonin transporter (5-HTTLPR)
18.  Distinct effects of ASD and ADHD symptoms on reward anticipation in participants with ADHD, their unaffected siblings and healthy controls: a cross-sectional study 
Molecular Autism  2015;6:48.
Background
Autism spectrum disorder (ASD) traits are continuously distributed throughout the population, and ASD symptoms are also frequently observed in patients with attention-deficit/hyperactivity disorder (ADHD). Both ASD and ADHD have been linked to alterations in reward-related neural processing. However, whether both symptom domains interact and/or have distinct effects on reward processing in healthy and ADHD populations is currently unknown.
Methods
We examined how variance in ASD and ADHD symptoms in individuals with ADHD and healthy participants was related to the behavioural and neural response to reward during a monetary incentive delay (MID) task. Participants (mean age: 17.7 years, range: 10–28 years) from the NeuroIMAGE study with a confirmed diagnosis of ADHD (n = 136), their unaffected siblings (n = 83), as well as healthy controls (n = 105) performed an MID task in a magnetic resonance imaging (MRI) scanner. ASD and ADHD symptom scores were used as predictors of the neural response to reward anticipation and reward receipt. Behavioural responses were modeled using linear mixed models; neural responses were analysed using FMRIB’s Software Library (FSL) proprietary mixed effects analysis (FLAMEO).
Results
ASD and ADHD symptoms were associated with alterations in BOLD activity during reward anticipation, but not reward receipt. Specifically, ASD scores were related to increased insular activity during reward anticipation across the sample. No interaction was found between this effect and the presence of ADHD, suggesting that ASD symptoms had no differential effect in ADHD and healthy populations. ADHD symptom scores were associated with reduced dorsolateral prefrontal activity during reward anticipation. No interactions were found between the effects of ASD and ADHD symptoms on reward processing.
Conclusions
Variance in ASD and ADHD symptoms separately influence neural processing during reward anticipation in both individuals with (an increased risk of) ADHD and healthy participants. Our findings therefore suggest that both symptom domains affect reward processing through distinct mechanisms, underscoring the importance of multidimensional and multimodal assessment in psychiatry.
Electronic supplementary material
The online version of this article (doi:10.1186/s13229-015-0043-y) contains supplementary material, which is available to authorized users.
doi:10.1186/s13229-015-0043-y
PMCID: PMC4551566  PMID: 26322219
ADHD; ASD; Reward; Reward anticipation; Comorbidity
19.  Psychosocial profile of pediatric brain tumor survivors with neurocognitive complaints 
Quality of Life Research  2015;25:435-446.
Purpose
With more children surviving a brain tumor, neurocognitive consequences of the tumor and its treatment become apparent, which could affect psychosocial functioning. The present study therefore aimed to assess psychosocial functioning of pediatric brain tumor survivors (PBTS) in detail.
Methods
Psychosocial functioning of PBTS (8–18 years) with parent-reported neurocognitive complaints was compared to normative data on health-related quality of life (HRQOL), self-esteem, psychosocial adjustment, and executive functioning (one-sample t tests) and to a sibling control group on fatigue (independent-samples t test). Self-, parent-, and teacher-report questionnaires were included, where appropriate, providing complementary information.
Results
Eighty-two PBTS (mean age 13.4 years, SD 3.2, 49 % males) and 43 healthy siblings (mean age 14.3, SD 2.4, 40 % males) were included. As compared to the normative population, PBTS themselves reported decreased physical, psychological, and generic HRQOL (d = 0.39–0.62, p < 0.008). Compared to siblings, increased fatigue-related concentration problems (d = 0.57, p < 0.01) were reported, although self-reported self-esteem and psychosocial adjustment seemed not to be affected. Parents of PBTS reported more psychosocial (d = 0.81, p < 0.000) and executive problems (d = 0.35–0.43, p < 0.016) in their child than parents of children in the normative population. Teachers indicated more psychosocial adjustment problems for female PBTS aged 8–11 years than for the female normative population (d = 0.69, p < 0.025), but they reported no more executive problems.
Conclusions
PBTS with parent-reported neurocognitive complaints showed increased psychosocial problems, as reported by PBTS, parents, and teachers.
Implications for cancer survivors
Systematic screening of psychosocial functioning is necessary so that tailored support from professionals can be offered to PBTS with neurocognitive complaints.
doi:10.1007/s11136-015-1091-7
PMCID: PMC4722086  PMID: 26289022
Brain tumor; Pediatric oncology; Psychosocial; Late effects of cancer treatment; Quality of life
20.  Diabetes IN develOpment (DINO): the bio-psychosocial, family functioning and parental well-being of youth with type 1 diabetes: a longitudinal cohort study design 
BMC Pediatrics  2015;15:82.
Background
Strict glycemic control during adolescence decreases the risk of developing complications later in life, even if this level of control is not maintained afterwards. However, the majority of adolescents with type 1 diabetes (T1D) are in poor control and so far medical or psychological interventions have shown limited success. Adolescence is characterized by major biological, psychosocial, cognitive and parent–child relationship changes and the complex interaction between these developmental trajectories, and its impact on health outcomes is still poorly understood. A specific topic of interest in this context is the timing of diagnosis. The longitudinal study DINO (Diabetes IN develOpment) aims to examine:If and how the onset of T1D before vs. during puberty results in different outcomes of glycemic control, self-management, psychological functioning and diabetes-related quality of life.The timing of onset of disturbed eating behavior, its risk factors and its prospective course in relation to glycemic and psychological consequences.If and how the onset of T1D before vs. during puberty results in different family functioning and parental well-being.If and how the cognitive development of youth with T1D relates to glycemic control and diabetes self-management.
Methods/design
DINO, a longitudinal multi-center cohort study is conducted in youth with T1D in the age range 8–15 years at baseline. Participants will be divided into two subgroups: pre-pubertal and pubertal. Both groups will be followed for 3 years with assessments based on a bio-psychosocial model of diabetes, scheduled at baseline, 12 months, 24 months and 36 months examining the biological, psychosocial -including disturbed eating behaviors- and cognitive development, family functioning and parental well-being.
Discussion
A better understanding of how the different trajectories affect one another will help to gain insight in the protective and risk factors for glycemic outcomes and in who needs which support at what moment in time. First results are expected in 2016.
Electronic supplementary material
The online version of this article (doi:10.1186/s12887-015-0400-1) contains supplementary material, which is available to authorized users.
doi:10.1186/s12887-015-0400-1
PMCID: PMC4502615  PMID: 26173476
Type 1 diabetes; Development; Youth; Quality of life; Well-being; Adolescence; Cognition; HbA1c; Psychosocial; Parents
21.  Neural activation patterns during response inhibition distinguish adolescents with ADHD, their unaffected siblings, and healthy controls 
The American journal of psychiatry  2015;172(7):674-683.
Objective
Impaired response inhibition is a key executive function deficit of attention-deficit/hyperactivity disorder (ADHD). Still, behavioral response inhibition measures do not consistently differentiate individuals with ADHD from unaffected individuals. We therefore investigated the neural correlates of response inhibition as well as the familial nature of these neural correlates.
Methods
fMRI measurements of neural activation during the stop-signal task along with behavioral measures of response inhibition were obtained in adolescents and young adults with ADHD (N=185), their unaffected siblings (N=111), and healthy controls (N=124).
Results
Stop-signal reaction times were longer in participants with ADHD, but not in their unaffected siblings, while reaction time variability and error rates were higher in both groups than in controls. Neural hypoactivation was observed in frontal-striatal and frontal-parietal networks of participants with ADHD and unaffected siblings compared to controls, whereby activation in inferior frontal and temporal/parietal nodes in unaffected siblings was intermediate between that of participants with ADHD and controls. Furthermore, neural activation in inferior frontal nodes correlated with stop-signal reaction times, and activation in both inferior frontal and temporal/parietal nodes correlated with ADHD severity.
Conclusions
Neural activation alterations in ADHD are more robust than behavioral response inhibition deficits and explain variance in response inhibition and ADHD severity. Although only affected participants with ADHD have deficient response inhibition, hypoactivation in inferior frontal and temporal-parietal nodes in unaffected siblings support the familial nature of the underlying neural process. Hypoactivation in these nodes may be useful as endophenotypes that extend beyond the affected individuals in the family.
doi:10.1176/appi.ajp.2014.13121635
PMCID: PMC4490085  PMID: 25615565
22.  A Follow-Up Study of Maternal Expressed Emotion Toward Children With Attention-Deficit/Hyperactivity Disorder (ADHD): Relation With Severity and Persistence of ADHD and Comorbidity 
Objective
Attention-deficit/hyperactivity disorder (ADHD) is associated with conflicted parent–child relationships. The underlying mechanisms of this association are not yet fully understood. We investigated the cross-sectional and longitudinal relationships between externalizing psychopathology in children with ADHD, and expressed emotion (EE; warmth and criticism) and psychopathology in mothers.
Method
In this 6-year follow-up study 385 children with an ADHD combined subtype were included at baseline (mean=11.5 years, 83.4% male), of which 285 children (74%) were available at follow-up (mean=17.5 years, 83.5% male). At both time points, measures of child psychopathology (i.e., ADHD severity, oppositional, and conduct problems), maternal EE, and maternal psychopathology (i.e., ADHD and affective problems) were obtained.
Results
EE was not significantly correlated over time. At baseline, we found a nominally negative association (p≤.05) between maternal warmth and child ADHD severity. At follow-up, maternal criticism was significantly associated with child oppositional problems, and nominally with child conduct problems. Maternal warmth was nominally associated with child oppositional and conduct problems. These associations were independent of maternal psychopathology. No longitudinal associations were found between EE at baseline and child psychopathology at follow-up, or child psychopathology at baseline and EE at follow-up.
Conclusions
The results support previous findings of cross-sectional associations between parental EE and child psychopathology. This, together with the finding that EE was not stable over six years, suggests that EE is a momentary state measure varying with contextual and developmental factors. EE does not appear to be a risk factor for later externalizing behavior in children with ADHD.
doi:10.1016/j.jaac.2013.11.011
PMCID: PMC4066112  PMID: 24565358
attention-deficit/hyperactivity disorder (ADHD); conduct problems; follow-up study; maternal expressed emotion; oppositional problems
23.  Altered neural connectivity during response inhibition in adolescents with attention-deficit/hyperactivity disorder and their unaffected siblings 
NeuroImage : Clinical  2015;7:325-335.
Introduction
Response inhibition is one of the executive functions impaired in attention-deficit/hyperactivity disorder (ADHD). Increasing evidence indicates that altered functional and structural neural connectivity are part of the neurobiological basis of ADHD. Here, we investigated if adolescents with ADHD show altered functional connectivity during response inhibition compared to their unaffected siblings and healthy controls.
Methods
Response inhibition was assessed using the stop signal paradigm. Functional connectivity was assessed using psycho-physiological interaction analyses applied to BOLD time courses from seed regions within inferior- and superior frontal nodes of the response inhibition network. Resulting networks were compared between adolescents with ADHD (N = 185), their unaffected siblings (N = 111), and controls (N = 125).
Results
Control subjects showed stronger functional connectivity than the other two groups within the response inhibition network, while subjects with ADHD showed relatively stronger connectivity between default mode network (DMN) nodes. Stronger connectivity within the response inhibition network was correlated with lower ADHD severity, while stronger connectivity with the DMN was correlated with increased ADHD severity. Siblings showed connectivity patterns similar to controls during successful inhibition and to ADHD subjects during failed inhibition. Additionally, siblings showed decreased connectivity with the primary motor areas as compared to both participants with ADHD and controls.
Discussion
Subjects with ADHD fail to integrate activation within the response inhibition network and to inhibit connectivity with task-irrelevant regions. Unaffected siblings show similar alterations only during failed stop trials, as well as unique suppression of motor areas, suggesting compensatory strategies. These findings support the role of altered functional connectivity in understanding the neurobiology and familial transmission of ADHD.
Highlights
•We investigate the neural connectivity during response inhibition using PPI.•We investigate connectivity in participants with ADHD, their siblings and controls.•Participants with ADHD show lower connectivity within the response inhibition network.•Participants with ADHD show higher connectivity with the default mode network.•Unaffected siblings show unique patterns of compensatory activation.
doi:10.1016/j.nicl.2015.01.004
PMCID: PMC4297885  PMID: 25610797
ADHD, attention deficit/hyperactivity disorder; CD, conduct disorder; DMN, default mode network; GEE, generalized estimating equations; ICV, intraindividual coefficient of variance; ODD, oppositional defiant disorder; RD, reading disorder; ROI, region of interest; SSRT, stop-signal reaction time; SST, Stop-signal task; SI, supplementary information; WM, white matter; ADHD; PPI; Connectivity; Siblings; Response inhibition
24.  Brain Volumetric Correlates of Autism Spectrum Disorder Symptoms in Attention Deficit/Hyperactivity Disorder 
PLoS ONE  2014;9(6):e101130.
Autism spectrum disorder (ASD) symptoms frequently occur in subjects with attention deficit/hyperactivity disorder (ADHD). While there is evidence that both ADHD and ASD have differential structural correlates, no study to date has investigated these structural correlates within a framework that robustly accounts for the phenotypic overlap between the two disorders. The presence of ASD symptoms was measured by the parent-reported Children’s Social and Behavioural Questionnaire (CSBQ) in ADHD subjects (n = 180), their unaffected siblings (n = 118) and healthy controls (n = 146). ADHD symptoms were assessed by a structured interview (K-SADS-PL) and the Conners’ ADHD questionnaires. Whole brain T1-weighted MPRAGE images were acquired and the structural MRI correlates of ASD symptom scores were analysed by modelling ASD symptom scores against white matter (WM) and grey matter (GM) volumes using mixed effects models which controlled for ADHD symptom levels. ASD symptoms were significantly elevated in ADHD subjects relative to both controls and unaffected siblings. ASD scores were predicted by the interaction between WM and GM volumes. Increasing ASD score was associated with greater GM volume. Equivocal results from previous structural studies in ADHD and ASD may be due to the fact that comorbidity has not been taken into account in studies to date. The current findings stress the need to account for issues of ASD comorbidity in ADHD.
doi:10.1371/journal.pone.0101130
PMCID: PMC4076257  PMID: 24979066
25.  Executive Functioning in Highly Talented Soccer Players 
PLoS ONE  2014;9(3):e91254.
Executive functions might be important for successful performance in sports, particularly in team sports requiring quick anticipation and adaptation to continuously changing situations in the field. The executive functions motor inhibition, attention and visuospatial working memory were examined in highly talented soccer players. Eighty-four highly talented youth soccer players (mean age 11.9), and forty-two age-matched amateur soccer players (mean age 11.8) in the age range 8 to 16 years performed a Stop Signal task (motor inhibition), the Attention Network Test (alerting, orienting, and executive attention) and a visuospatial working memory task. The highly talented soccer players followed the talent development program of the youth academy of a professional soccer club and played at the highest national soccer competition for their age. The amateur soccer players played at a regular soccer club in the same geographical region as the highly talented soccer players and play in a regular regional soccer competition. Group differences were tested using analyses of variance. The highly talented group showed superior motor inhibition as measured by stop signal reaction time (SSRT) on the Stop Signal task and a larger alerting effect on the Attention Network Test, indicating an enhanced ability to attain and maintain an alert state. No group differences were found for orienting and executive attention and visuospatial working memory. A logistic regression model with group (highly talented or amateur) as dependent variable and executive function measures that significantly distinguished between groups as predictors showed that these measures differentiated highly talented soccer players from amateur soccer players with 89% accuracy. Highly talented youth soccer players outperform youth amateur players on suppressing ongoing motor responses and on the ability to attain and maintain an alert state; both may be essential for success in soccer.
doi:10.1371/journal.pone.0091254
PMCID: PMC3954684  PMID: 24632735

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