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.

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.

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.

Genetic predisposition, autoimmunity and environmental factors [e.g. pre- and perinatal difficulties, Group A Streptococcal (GAS) and other infections, stress-inducing events] might interact to create a neurobiological vulnerability to the development of tics and associated behaviours. However, the existing evidence for this relies primarily on small prospective or larger retrospective population-based studies, and is therefore still inconclusive. This article describes the design and methodology of the EMTICS study, a longitudinal observational European multicentre study involving 16 clinical centres, with the following objectives: (1) to investigate the association of environmental factors (GAS exposure and psychosocial stress, primarily) with the onset and course of tics and/or obsessive-compulsive symptoms through the prospective observation of at-risk individuals (ONSET cohort: 260 children aged 3-10 years who are tic-free at study entry and have a first-degree relative with a chronic tic disorder) and affected individuals (COURSE cohort: 715 youth aged 3-16 years with a tic disorder); (2) to characterise the immune response to microbial antigens and the host's immune response regulation in association with onset and exacerbations of tics; (3) to increase knowledge of the human gene pathways influencing the pathogenesis of tic disorders; and (4) to develop prediction models for the risk of onset and exacerbations of tic disorders. The EMTICS study is, to our knowledge, the largest prospective cohort assessment of the contribution of different genetic and environmental factors to the risk of developing tics in putatively predisposed individuals and to the risk of exacerbating tics in young individuals with chronic tic disorders.

Tourette syndrome (TS) has a well-established genetic background, but its genetic architecture remains largely unknown. The authors investigated the role of polygenic risk scores (PRSs) derived from a TS genome-wide association study in relation to the occurrence of tics and associated traits in a general population cohort.

Maladaptive aggression, as present in conduct disorder (CD) and, to a lesser extent, oppositional defiant disorder (ODD), has been associated with structural alterations in various brain regions, such as ventromedial prefrontal cortex (vmPFC), anterior cingulate cortex (ACC), amygdala, insula and ventral striatum. Although aggression can be subdivided into reactive and proactive subtypes, no neuroimaging studies have yet investigated if any structural brain alterations are associated with either of the subtypes specifically. Here we investigated associations between aggression subtypes, CU traits and ADHD symptoms in predefined regions of interest. T1-weighted magnetic resonance images were acquired from 158 children and adolescents with disruptive behavior (ODD/CD) and 96 controls in a multi-center study (aged 8-18). Aggression subtypes were assessed by questionnaires filled in by participants and their parents. Cortical volume and subcortical volumes and shape were determined using Freesurfer and the FMRIB integrated registration and segmentation tool. Associations between volumes and continuous measures of aggression were established using multilevel linear mixed effects models. Proactive aggression was negatively associated with amygdala volume (b = -10.7, p = 0.02), while reactive aggression was negatively associated with insula volume (b = -21.7, p = 0.01). No associations were found with CU traits or ADHD symptomatology. Classical group comparison showed that children and adolescents with disruptive behavior had smaller volumes than controls in (bilateral) vmPFC (p = 0.003) with modest effect size and a reduced shape in the anterior part of the left ventral striatum (p = 0.005). Our study showed negative associations between reactive aggression and volumes in a region involved in threat responsivity and between proactive aggression and a region linked to empathy. This provides evidence for aggression subtype-specific alterations in brain structure which may provide useful insights for clinical practice.

In a recent meta-analysis, we found that atopic diseases, like asthma and allergic rhinitis, occur more frequently prior to the onset of attention-deficit/hyperactivity disorder (ADHD). Our aim was to determine the temporal order of the association between daily fluctuations in atopic disease symptoms and in ADHD symptoms in individual participants. In this observational study among 21 participants, age 7-16 years, we performed a replicated time-series analysis of symptom fluctuations in asthma and/or allergic rhinitis and ADHD. Data were collected through parents who filled in a daily online questionnaire during up to 50 days. In each individual, we investigated the temporal order of fluctuations in atopic disease symptoms and ADHD symptoms using a vector autoregressive (VAR) model while using sleep problems and medication use as covariates. For 16 out of 21 participants, we constructed a VAR model. For a majority of the participants, significant associations were detected between atopic disease symptoms and ADHD symptoms. The results were heterogeneous; the direction, sign, and timing of the relationship between ADHD, atopy, sleep problems, and medication use varied between individuals. This study provides additional evidence that the symptom expression of atopy and ADHD are related. However, the connection between both diseases in children is found to be heterogeneous within our study population.

Objectives. This study aimed to assess the cost-effectiveness of treatments for attention-deficit/hyperactivity disorder (ADHD) in children through prevention of serious delinquent behavior. Cost-effectiveness was assessed in net-monetary benefit (NMB). Methods. To evaluate the three major forms of ADHD treatment (medication management, behavioral treatment, and the combination thereof) relative to community-delivered treatment (control condition), we used data from 448 children, aged 7 to 10, who participated in the National Institute of Mental Health's Multimodal Treatment Study of Children with ADHD. We developed a three-state continuous-time Markov model (no delinquency, minor to moderate delinquency, serious delinquency) to extrapolate the results 10 years beyond the 14-month trial period at a 3% discount rate. Serious delinquency was considered an absorbing state to enable assessment in life-years (LYs) of serious delinquent behavior prevented. The willingness-to-pay (WTP) threshold was set equal to the annual cost associated with serious delinquency in children with ADHD of $12,370. Results. Modeled and observed outcomes matched closely with a mean difference of 6.9% in LYs of serious delinquent behavior prevented. The economic evaluation revealed a NMB of $95,449, $88,553, $90,536 and $98,660 for medication management, behavioral treatment, combined treatment, and routine community care, respectively. Estimates remained stable after linearly increasing the WTP threshold between $0 and $50,000 in the deterministic sensitivity analyses. Conclusions. This study assessed the cost-effectiveness of treatments for ADHD in children using continuous-time Markov modeling. We show that treatment evaluation in broader societal outcomes is essential for policy makers, as the three major forms of ADHD treatment turned out to be inferior to the control condition.

This study aimed to examine the associations between individual staff and staff team characteristics and quality of life of individuals with intellectual disabilities and challenging behaviours.

Attention-Deficit/Hyperactivity Disorder (ADHD) has been associated with altered brain anatomy in neuroimaging studies. However, small and heterogeneous study samples, and the use of region-of-interest and tissue-specific analyses have limited the consistency and replicability of these effects. We used a data-driven multivariate approach to investigate neuroanatomical features associated with ADHD in two independent cohorts: the Dutch NeuroIMAGE cohort (n = 890, 17.2 years) and the Brazilian IMpACT cohort (n = 180, 44.2 years). Using independent component analysis of whole-brain morphometry images, 375 neuroanatomical components were assessed for association with ADHD. In both discovery (corrected-p = 0.0085) and replication (p = 0.032) cohorts, ADHD was associated with reduced volume in frontal lobes, striatum, and their interconnecting white-matter. Current results provide further evidence for the role of the fronto-striatal circuit in ADHD in children, and for the first time show its relevance to ADHD in adults. The fact that the cohorts are from different continents and comprise different age ranges highlights the robustness of the findings.

Morphology of the human cerebral cortex differs across psychiatric disorders, with neurobiology and developmental origins mostly undetermined. Deviations in the tangential growth of the cerebral cortex during pre/perinatal periods may be reflected in individual variations in cortical surface area later in life.

Impaired emotion recognition is common in individuals with attention-deficit/hyperactivity disorder (ADHD) and may, via deficient emotion self-regulation, relate to the frequently co-occurring affective and social problems. The present study used an emotional face-matching task and functional magnetic resonance imaging (fMRI) to investigate neural responses during the processing of angry and fearful faces and visuo-spatial control stimuli. Additionally, measures for emotion dysregulation, ADHD type, and age were investigated in relation to the behavioral and neural fMRI data. We utilized a sample of 61 adolescents/young adults with ADHD and 51 age-matched healthy controls (age range: 12-28 years). Participants with ADHD had higher emotion dysregulation scores than controls. They also reacted slower and less accurate in response to emotional but not visuo-spatial control stimuli. Neural response differences between emotional and visuo-spatial trials were significantly smaller in cases, particularly in the left amygdala. While coupling between the right amygdala and bilateral ventromedial prefrontal cortex was stronger for emotional than visuo-spatial stimuli in control subjects, levels of positive coupling between the trial types did not significantly differ in participants with ADHD. Neither emotion dysregulation scores, nor ADHD type or age were related to the behavioral and neural processing alterations during the emotional face-matching task. Results indicate that emotion recognition deficits in ADHD are particularly associated with lower amygdala activation to emotional stimuli and alterations in the functional connections of the amygdala to medial prefrontal areas. Emotion recognition deficits and associated neural alterations were unrelated to emotion dysregulation, ADHD type, or age.

Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total N = 454; 8-29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity.

Autism spectrum disorder (ASD), Tourette syndrome (TS), and attention-deficit/hyperactivity disorder (ADHD) display strong male sex bias, due to a combination of genetic and biological factors, as well as selective ascertainment. While the hemizygous nature of chromosome X (Chr X) in males has long been postulated as a key point of "male vulnerability", rare genetic variation on this chromosome has not been systematically characterized in large-scale whole exome sequencing studies of "idiopathic" ASD, TS, and ADHD. Here, we take advantage of informative recombinations in simplex ASD families to pinpoint risk-enriched regions on Chr X, within which rare maternally-inherited damaging variants carry substantial risk in males with ASD. We then apply a modified transmission disequilibrium test to 13,052 ASD probands and identify a novel high confidence ASD risk gene at exome-wide significance (MAGEC3). Finally, we observe that rare damaging variants within these risk regions carry similar effect sizes in males with TS or ADHD, further clarifying genetic mechanisms underlying male vulnerability in multiple neurodevelopmental disorders that can be exploited for systematic gene discovery.

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.

Attention-deficit/hyperactivity disorder (ADHD) is associated with structural abnormalities in total gray matter, basal ganglia, and cerebellum. Findings of structural abnormalities in frontal and temporal lobes, amygdala, and insula are less consistent. Remarkably, the impact of comorbid oppositional defiant disorder (ODD) (comorbidity rates up to 60%) on these neuroanatomical differences is scarcely studied, while ODD (in combination with conduct disorder) has been associated with structural abnormalities of the frontal lobe, amygdala, and insula. The aim of this study was to investigate the effect of comorbid ODD on cerebral volume and cortical thickness in ADHD.

Magnetic resonance imaging (MRI) studies have highlighted subcortical, cortical, and structural connectivity abnormalities associated with attention-deficit/hyperactivity disorder (ADHD). Gyrification investigations of the cortex have been inconsistent and largely negative, potentially due to a lack of sensitivity of the previously used morphological parameters. The innovative approach of applying intrinsic curvature analysis, which is predictive of gyrification pattern, to the cortical surface applied herein allowed us greater sensitivity to determine whether the structural connectivity abnormalities thus far identified at a centimeter scale also occur at a millimeter scale within the cortical surface. This could help identify neurodevelopmental processes that contribute to ADHD. Structural MRI datasets from the NeuroIMAGE project were used [n = 306 ADHD, n = 164 controls, and n = 148 healthy siblings of individuals with ADHD (age in years, mean(sd); 17.2 (3.4), 16.8 (3.2), and 17.7 (3.8), respectively)]. Reconstructions of the cortical surfaces were computed with FreeSurfer. Intrinsic curvature (taken as a marker of millimeter-scale surface connectivity) and local gyrification index were calculated for each point on the surface (vertex) with Caret and FreeSurfer, respectively. Intrinsic curvature skew and mean local gyrification index were extracted per region; frontal, parietal, temporal, occipital, cingulate, and insula. A generalized additive model was used to compare the trajectory of these measures between groups over age, with sex, scanner site, total surface area of hemisphere, and familiality accounted for. After correcting for sex, scanner site, and total surface area no group differences were found in the developmental trajectory of intrinsic curvature or local gyrification index. Despite the increased sensitivity of intrinsic curvature, compared to gyrification measures, to subtle morphological abnormalities of the cortical surface we found no milimeter-scale connectivity abnormalities associated with ADHD.

Adolescence is a period of significant brain changes; however, the effects of age and sex on cortical development are yet to be fully characterized. Here, we utilized innovative intrinsic curvature (IC) analysis, along with the traditional cortical measures [cortical thickness (CT), local gyrification index (LGI), and surface area (SA)], to investigate how these indices (1) relate to each other and (2) depend on age and sex in adolescent cortical development. T1-weighted magnetic resonance images from 218 healthy volunteers (age range 8.3-29.2 years, M[SD] = 16.5[3.4]) were collected at two sites and processed with FreeSurfer and Caret software packages. Surface indices were extracted per cortex area (frontal, parietal, occipital, temporal, insula, and cingulate). Correlation analyses between the surface indices were conducted and age curves were modelled using generalized additive mixed-effect models. IC showed region-specific associations with LGI, SA, and CT, as did CT with LGI. SA was positively associated with LGI in all regions and CT in none. CT and LGI, but not SA, were inversely associated with age in all regions. IC was inversely associated with age in all but the occipital region. For all regions, males had larger cortical SA than females. Males also had larger LGI in all regions and larger IC of the frontal area; however, these effects were accounted for by sex differences in SA. There were no age-by-sex interactions. The study of IC adds a semi-independent, sensitive measure of cortical morphology that relates to the underlying cytoarchitecture and may aid understanding of normal brain development and deviations from it.

Common risk factors for psychiatric and other brain disorders are likely to converge on biological pathways influencing the development and maintenance of brain structure and function across life. Using structural MRI data from 45,615 individuals aged 3-96 years, we demonstrate distinct patterns of apparent brain aging in several brain disorders and reveal genetic pleiotropy between apparent brain aging in healthy individuals and common brain disorders.

Human brain structure changes throughout the lifespan. Altered brain growth or rates of decline are implicated in a vast range of psychiatric, developmental and neurodegenerative diseases. In this study, we identified common genetic variants that affect rates of brain growth or atrophy in what is, to our knowledge, the first genome-wide association meta-analysis of changes in brain morphology across the lifespan. Longitudinal magnetic resonance imaging data from 15,640 individuals were used to compute rates of change for 15 brain structures. The most robustly identified genes GPR139, DACH1 and APOE are associated with metabolic processes. We demonstrate global genetic overlap with depression, schizophrenia, cognitive functioning, insomnia, height, body mass index and smoking. Gene set findings implicate both early brain development and neurodegenerative processes in the rates of brain changes. Identifying variants involved in structural brain changes may help to determine biological pathways underlying optimal and dysfunctional brain development and aging.