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Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.

The genetic architecture underlying brainstem regions and how this links to common brain disorders is not well understood. Here, the authors use MRI and GWAS data from 27,034 individuals to identify genetic and morphological brainstem features that influence common brain disorders.

Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder that often persists into adulthood. ADHD and related personality traits, such as impulsivity and callousness, are caused by genetic and environmental factors and their interplay. Epigenetic modifications of DNA, including methylation, are thought to mediate between such factors and behavior and may behave as biomarkers for disorders. Here, we set out to study DNA methylation in persistent ADHD and related traits. We performed epigenome-wide association studies (EWASs) on peripheral whole blood from participants in the NeuroIMAGE study (age range 12–23 years). We compared participants with persistent ADHD (n = 35) with healthy controls (n = 19) and with participants with remittent ADHD (n = 19). Additionally, we performed EWASs of impulsive and callous traits derived from the Conners Parent Rating Scale and the Callous-Unemotional Inventory, respectively, across all participants. For every EWAS, the linear regression model analyzed included covariates for age, sex, smoking scores, and surrogate variables reflecting blood cell type composition and genetic background. We observed no epigenome-wide significant differences in single CpG site methylation between participants with persistent ADHD and healthy controls or participants with remittent ADHD. However, epigenome-wide analysis of differentially methylated regions provided significant findings showing that hypermethylated regions in the APOB and LPAR5 genes were associated with ADHD persistence compared to ADHD remittance (p = 1.68 * 10−24 and p = 9.06 * 10−7, respectively); both genes are involved in cholesterol signaling. Both findings appeared to be linked to genetic variation in cis. We found neither significant epigenome-wide single CpG sites nor regions associated with impulsive and callous traits; the top-hits from these analyses were annotated to genes involved in neurotransmitter release and the regulation of the biological clock. No link to genetic variation was observed for these findings, which thus might reflect environmental influences. In conclusion, in this pilot study with a small sample size, we observed several DNA-methylation–disorder/trait associations of potential significance for ADHD and the related behavioral traits. Although we do not wish to draw conclusions before replication in larger, independent samples, cholesterol signaling and metabolism may be of relevance for the onset and/or persistence of ADHD.

Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity.

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.

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.

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.

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.

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.

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.

Previous research has shown that the extent to which people spread attention across the visual field plays a crucial role in visual selection and the occurrence of bottom-up driven attentional capture. Consistent with previous findings, we show that when attention was diffusely distributed across the visual field while searching for a shape singleton, an irrelevant salient color singleton captured attention. However, while using the very same displays and task, no capture was observed when observers initially focused their attention at the center of the display. Using event-related fMRI, we examined the modulation of retinotopic activity related to attentional capture in early visual areas. Because the sensory display characteristics were identical in both conditions, we were able to isolate the brain activity associated with exogenous attentional capture. The results show that spreading of attention leads to increased bottom-up exogenous capture and increased activity in visual area V3 but not in V2 and V1.