Anxiety, mood, and substance use disorders in adult men and women with and without attention-deficit/hyperactivity disorder: A substantive and methodological overview.

Knowledge on psychiatric comorbidity in adult ADHD is essential for prevention, detection, and treatment of these conditions. This review (1) focuses on large studies (n > 10,000; surveys, claims data, population registries) to identify (a) overall, (b) sex- and (c) age-specific patterns of comorbidity of anxiety disorders (ADs), major depressive disorder (MDD), bipolar disorder (BD) and substance use disorders (SUDs) in adults with ADHD relative to adults without ADHD; and (2) describes methodological challenges relating to establishing comorbidity in ADHD in adults as well as priorities for future research. Meta-analyses (ADHD: n = 550,748; no ADHD n = 14,546,814) yielded pooled odds ratios of 5.0(CI:3.29-7.46) for ADs, 4.5(CI:2.44-8.34) for MDD, 8.7(CI:5.47-13.89) for BD and 4.6(CI:2.72-7.80) for SUDs, indicating strong differences in adults with compared to adults without ADHD. Moderation by sex was not found: high comorbidity held for both men and women with sex-specific patterns as in the general population: higher prevalences of ADs, MDD and BD in women and a higher prevalence of SUDs in men. Insufficient data on different phases of the adult lifespan prevented conclusions on developmental changes in comorbidity. We discuss methodological challenges, knowledge gaps, and future research priorities.

A qualitative and quantitative study of self-reported positive characteristics of individuals with ADHD.

Research in Attention-deficit/hyperactivity disorder (ADHD) has had a clear focus on treatment and the dysfunction in specific situation associated with the condition. However, self-report, observational and anecdotal evidence indicates that there are also positive aspects associated with ADHD. Research on the potential positive features in individuals with an ADHD diagnosis is still limited, especially studies with larger representative samples. Here we performed qualitative research to identify positive aspects and strengths associated with ADHD in a large convenience sample from the Dutch organization for people with ADHD, dyslexia and dyscalculia. We sent out open-ended questionnaires to the members of the organization, asking what they consider to be positive aspects of their ADHD. From the responses of individuals with ADHD (n = 206), we extracted 116 codes, which were assigned to thirteen subthemes, which in turn led to five themes. These themes were: Creativity, Being dynamic, Flexibility, Socio-affective skills, and Higher-order cognitive skills. Core symptoms of ADHD such as impulsivity and hyperactivity were also considered positive aspects of ADHD by a minority of participants. After showing our results to a group of additional individuals with ADHD (focus group) they confirmed the identified positive aspects of ADHD. They also helped us with the interpretation of our findings and mentioned certain positive aspects to be a consequence of living with ADHD (being open minded and being honest). In conclusion, experiencing positive aspects seems to be common in ADHD as almost all participants reported positive aspect of ADHD, these aspects cover many different domains. Awareness about ADHD's strengths might help individuals with ADHD and their environment to better cope with, accept or embrace their diagnosis and for example make educational or occupational choices that fit them well. To incorporate these positive aspects in the understanding of ADHD, future research should focus on quantifying strengths in ADHD, and on investigating the link between these aspects and clinical characteristics and how this new knowledge can be implemented in psychoeducation and find its way to education and occupational settings.

The Role of the Gut-Brain Axis in Attention-Deficit/Hyperactivity Disorder.

Genetic and environmental factors play a role in the cause and development of attention-deficit/hyperactivity disorder (ADHD). Recent studies have suggested an important role of the gut-brain axis (GBA) and intestinal microbiota in modulating the risk of ADHD. Here, the authors provide a brief overview of the clinical and biological picture of ADHD and how the GBA could be involved in its cause. They discuss key biological mechanisms involved in the GBA and how these may increase the risk of developing ADHD. Understanding these mechanisms may help to characterize novel treatment options via identification of disease biomarkers.

Similar Subgroups Based on Cognitive Performance Parse Heterogeneity in Adults With ADHD and Healthy Controls.

OBJECTIVE: To characterize heterogeneity in adults with ADHD we aimed to identify subgroups within the adult ADHD spectrum, which differ in their cognitive profile. METHOD: Neuropsychological data from adults with ADHD ( n = 133) and healthy control participants ( n = 132) were used in a confirmatory factor analysis. The resulting six cognitive factors were correlated across participants to form networks. We used a community detection algorithm to cluster these networks into subgroups. RESULTS: Both the ADHD and control group separated into three profiles that differed in cognitive performance. Profile 1 was characterized by aberrant attention and inhibition, profile 2 by increased delay discounting, and profile 3 by atypical working memory and verbal fluency. CONCLUSION: Our findings suggest that qualitative differences in neuropsychological performance exist in both control and ADHD adult individuals. This extends prior findings in children with and without ADHD and provides a framework to parse participants into well-defined subgroups.

Subcortical brain volume differences in participants with attention deficit hyperactivity disorder in children and adults: a cross-sectional mega-analysis.

BACKGROUND: Neuroimaging studies have shown structural alterations in several brain regions in children and adults with attention deficit hyperactivity disorder (ADHD). Through the formation of the international ENIGMA ADHD Working Group, we aimed to address weaknesses of previous imaging studies and meta-analyses, namely inadequate sample size and methodological heterogeneity. We aimed to investigate whether there are structural differences in children and adults with ADHD compared with those without this diagnosis. METHODS: In this cross-sectional mega-analysis, we used the data from the international ENIGMA Working Group collaboration, which in the present analysis was frozen at Feb 8, 2015. Individual sites analysed structural T1-weighted MRI brain scans with harmonised protocols of individuals with ADHD compared with those who do not have this diagnosis. Our primary outcome was to assess case-control differences in subcortical structures and intracranial volume through pooling of all individual data from all cohorts in this collaboration. For this analysis, p values were significant at the false discovery rate corrected threshold of p=0·0156. FINDINGS: Our sample comprised 1713 participants with ADHD and 1529 controls from 23 sites with a median age of 14 years (range 4-63 years). The volumes of the accumbens (Cohen's d=-0·15), amygdala (d=-0·19), caudate (d=-0·11), hippocampus (d=-0·11), putamen (d=-0·14), and intracranial volume (d=-0·10) were smaller in individuals with ADHD compared with controls in the mega-analysis. There was no difference in volume size in the pallidum (p=0·95) and thalamus (p=0·39) between people with ADHD and controls. Exploratory lifespan modelling suggested a delay of maturation and a delay of degeneration, as effect sizes were highest in most subgroups of children (<15 years) versus adults (>21 years): in the accumbens (Cohen's d=-0·19 vs -0·10), amygdala (d=-0·18 vs -0·14), caudate (d=-0·13 vs -0·07), hippocampus (d=-0·12 vs -0·06), putamen (d=-0·18 vs -0·08), and intracranial volume (d=-0·14 vs 0·01). There was no difference between children and adults for the pallidum (p=0·79) or thalamus (p=0·89). Case-control differences in adults were non-significant (all p>0·03). Psychostimulant medication use (all p>0·15) or symptom scores (all p>0·02) did not influence results, nor did the presence of comorbid psychiatric disorders (all p>0·5). INTERPRETATION: With the largest dataset to date, we add new knowledge about bilateral amygdala, accumbens, and hippocampus reductions in ADHD. We extend the brain maturation delay theory for ADHD to include subcortical structures and refute medication effects on brain volume suggested by earlier meta-analyses. Lifespan analyses suggest that, in the absence of well powered longitudinal studies, the ENIGMA cross-sectional sample across six decades of ages provides a means to generate hypotheses about lifespan trajectories in brain phenotypes. FUNDING: National Institutes of Health.

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

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

Characterising resting-state functional connectivity in a large sample of adults with ADHD.

Attention-deficit/hyperactivity disorder (ADHD) is a common childhood psychiatric disorder that often persists into adulthood. While several studies have identified altered functional connectivity in brain networks during rest in children with ADHD, few studies have been performed on adults with ADHD. Existing studies have generally investigated small samples. We therefore investigated aberrant functional connectivity in a large sample of adult patients with childhood-onset ADHD, using a data-driven, whole-brain approach. Adults with a clinical ADHD diagnosis (N=99) and healthy, adult comparison subjects (N=113) underwent a 9-minute resting-state fMRI session in a 1.5T MRI scanner. After elaborate preprocessing including a thorough head-motion correction procedure, group independent component analysis (ICA) was applied from which we identified six networks of interest: cerebellum, executive control, left and right frontoparietal and two default-mode networks. Participant-level network maps were obtained using dual-regression and tested for differences between patients with ADHD and controls using permutation testing. Patients showed significantly stronger connectivity in the anterior cingulate gyrus of the executive control network. Trends were also observed for stronger connectivity in the cerebellum network in ADHD patients compared to controls. However, there was considerable overlap in connectivity values between patients and controls, leading to relatively low effect sizes despite the large sample size. These effect sizes were slightly larger when testing for correlations between hyperactivity/impulsivity symptoms and connectivity strength in the executive control and cerebellum networks. This study provides important insights for studies on the neurobiology of adult ADHD; it shows that resting-state functional connectivity differences between adult patients and controls exist, but have smaller effect sizes than existing literature suggested.

Cognitive heterogeneity in adult attention deficit/hyperactivity disorder: A systematic analysis of neuropsychological measurements.

Attention Deficit/Hyperactivity Disorder (ADHD) in childhood is associated with impaired functioning in multiple cognitive domains: executive functioning (EF), reward and timing. Similar impairments have been described for adults with persistent ADHD, but an extensive investigation of neuropsychological functioning in a large sample of adult patients is currently lacking. We systematically examined neuropsychological performance on tasks measuring EF, delay discounting, time estimation and response variability using univariate ANCOVA's comparing patients with persistent ADHD (N=133, 42% male, mean age 36) and healthy adults (N=132, 40% male, mean age 36). In addition, we tested which combination of variables provided the highest accuracy in predicting ADHD diagnosis. We also estimated for each individual the severity of neuropsychological dysfunctioning. Lastly, we investigated potential effects of stimulant medication and a history of comorbid major depressive disorder (MDD) on performance. Compared to healthy adults, patients with ADHD showed impaired EF, were more impulsive, and more variable in responding. However, effect sizes were small to moderate (range: 0.05-0.70) and 11% of patients did not show neuropsychological dysfunctioning. The best fitting model predicting ADHD included measures from distinct cognitive domains (82.1% specificity, 64.9% sensitivity). Furthermore, patients receiving stimulant medication or with a history of MDD were not distinctively impaired. To conclude, while adults with ADHD as a group are impaired on several cognitive domains, the results confirm that adult ADHD is neuropsychologically heterogeneous. This provides a starting point to investigate individual differences in terms of impaired cognitive pathways.

Lower white matter microstructure in the superior longitudinal fasciculus is associated with increased response time variability in adults with attention-deficit/ hyperactivity disorder.

BACKGROUND: Response time variability (RTV) is consistently increased in patients with attention-deficit/hyperactivity disorder (ADHD). A right-hemispheric frontoparietal attention network model has been implicated in these patients. The 3 main connecting fibre tracts in this network, the superior longitudinal fasciculus (SLF), inferior longitudinal fasciculus (ILF) and the cingulum bundle (CB), show microstructural abnormalities in patients with ADHD. We hypothesized that the microstructural integrity of the 3 white matter tracts of this network are associated with ADHD and RTV. METHODS: We examined RTV in adults with ADHD by modelling the reaction time distribution as an exponentially modified Gaussian (ex-Gaussian) function with the parameters µ, σ and τ, the latter of which has been attributed to lapses of attention. We assessed adults with ADHD and healthy controls using a sustained attention task. Diffusion tensor imaging-derived fractional anisotropy (FA) values were determined to quantify bilateral microstructural integrity of the tracts of interest. RESULTS: We included 100 adults with ADHD and 96 controls in our study. Increased τ was associated with ADHD diagnosis and was linked to symptoms of inattention. An inverse correlation of τ with mean FA was seen in the right SLF of patients with ADHD, but no direct association between the mean FA of the 6 regions of interest with ADHD could be observed. LIMITATIONS: Regions of interest were defined a priori based on the attentional network model for ADHD and thus we might have missed effects in other networks. CONCLUSION: This study suggests that reduced microstructural integrity of the right SLF is associated with elevated τ in patients with ADHD.

Deviant white matter structure in adults with attention-deficit/hyperactivity disorder points to aberrant myelination and affects neuropsychological performance.

Attention-deficit/hyperactivity disorder (ADHD) in childhood is characterized by gray and white matter abnormalities in several brain areas. Considerably less is known about white matter microstructure in adults with ADHD and its relation with clinical symptoms and cognitive performance. In 107 adult ADHD patients and 109 gender-, age- and IQ-matched controls, we used diffusion tensor imaging (DTI) with tract-based spatial statistics (TBSS) to investigate whole-skeleton changes of fractional anisotropy (FA) and mean, axial, and radial diffusivity (MD, AD, RD). Additionally, we studied the relation of FA and MD values with symptom severity and cognitive performance on tasks measuring working memory, attention, inhibition, and delay discounting. In comparison to controls, participants with ADHD showed reduced FA in corpus callosum, bilateral corona radiata, and thalamic radiation. Higher MD and RD were found in overlapping and even more widespread areas in both hemispheres, also encompassing internal and external capsule, sagittal stratum, fornix, and superior lateral fasciculus. Values of FA and MD were not associated with symptom severity. However, within some white matter clusters that distinguished patients from controls, worse inhibition performance was associated with reduced FA and more impulsive decision making was associated with increased MD. This study shows widespread differences in white matter integrity between adults with persistent ADHD and healthy individuals. Changes in RD suggest aberrant myelination as a pathophysiological factor in persistent ADHD. The microstructural differences in adult ADHD may contribute to poor inhibition and greater impulsivity but appear to be independent of disease severity.

Brain alterations in adult ADHD: effects of gender, treatment and comorbid depression.

Children with attention-deficit/hyperactivity disorder (ADHD) have smaller volumes of total brain matter and subcortical regions, but it is unclear whether these represent delayed maturation or persist into adulthood. We performed a structural MRI study in 119 adult ADHD patients and 107 controls and investigated total gray and white matter and volumes of accumbens, caudate, globus pallidus, putamen, thalamus, amygdala and hippocampus. Additionally, we investigated effects of gender, stimulant treatment and history of major depression (MDD). There was no main effect of ADHD on the volumetric measures, nor was any effect observed in a secondary voxel-based morphometry (VBM) analysis of the entire brain. However, in the volumetric analysis a significant gender by diagnosis interaction was found for caudate volume. Male patients showed reduced right caudate volume compared to male controls, and caudate volume correlated with hyperactive/impulsive symptoms. Furthermore, patients using stimulant treatment had a smaller right hippocampus volume compared to medication-naïve patients and controls. ADHD patients with previous MDD showed smaller hippocampus volume compared to ADHD patients with no MDD. While these data were obtained in a cross-sectional sample and need to be replicated in a longitudinal study, the findings suggest that developmental brain differences in ADHD largely normalize in adulthood. Reduced caudate volume in male patients may point to distinct neurobiological deficits underlying ADHD in the two genders. Smaller hippocampus volume in ADHD patients with previous MDD is consistent with neurobiological alterations observed in MDD.