Longitudinal changes of ADHD symptoms in association with white matter microstructure: A tract-specific fixel-based analysis.

BACKGROUND: Variation in the longitudinal course of childhood attention deficit/hyperactivity disorder (ADHD) coincides with neurodevelopmental maturation of brain structure and function. Prior work has attempted to determine how alterations in white matter (WM) relate to changes in symptom severity, but much of that work has been done in smaller cross-sectional samples using voxel-based analyses. Using standard diffusion-weighted imaging (DWI) methods, we previously showed WM alterations were associated with ADHD symptom remission over time in a longitudinal sample of probands, siblings, and unaffected individuals. Here, we extend this work by further assessing the nature of these changes in WM microstructure by including an additional follow-up measurement (aged 18 - 34 years), and using the more physiologically informative fixel-based analysis (FBA). METHODS: Data were obtained from 139 participants over 3 clinical and 2 follow-up DWI waves, and analyzed using FBA in regions-of-interest based on prior findings. We replicated previously reported significant models and extended them by adding another time-point, testing whether changes in combined ADHD and hyperactivity-impulsivity (HI) continuous symptom scores are associated with fixel metrics at follow-up. RESULTS: Clinical improvement in HI symptoms over time was associated with more fiber density at follow-up in the left corticospinal tract (lCST) (tmax = 1.092, standardized effect[SE] = 0.044, pFWE = 0.016). Improvement in combined ADHD symptoms over time was associated with more fiber cross-section at follow-up in the lCST (tmax = 3.775, SE = 0.051, pFWE = 0.019). CONCLUSIONS: Aberrant white matter development involves both lCST micro- and macrostructural alterations, and its path may be moderated by preceding symptom trajectory.

A randomised controlled trial (MindChamp) of a mindfulness-based intervention for children with ADHD and their parents.

BACKGROUND: Family mindfulness-based intervention (MBI) for child attention-deficit/hyperactivity disorder (ADHD) targets child self-control, parenting and parental mental health, but its effectiveness is still unclear. METHODS: MindChamp is a pre-registered randomised controlled trial comparing an 8-week family MBI (called 'MYmind') in addition to care-as-usual (CAU) (n = 55) with CAU-only (n = 48). Children aged 8-16 years with remaining ADHD symptoms after CAU were enrolled together with a parent. Primary outcome was post-treatment parent-rated child self-control deficits (BRIEF); post hoc, Reliable Change Indexes were explored. Secondary child outcomes included ADHD symptoms (parent/teacher-rated Conners' and SWAN; teacher-rated BRIEF), other psychological symptoms (parent/teacher-rated), well-being (parent-rated) and mindfulness (self-rated). Secondary parent outcomes included self-ratings of ADHD symptoms, other psychological symptoms, well-being, self-compassion and mindful parenting. Assessments were conducted at post-treatment, 2- and 6-month follow-up. RESULTS: Relative to CAU-only, MBI+CAU resulted in a small, statistically non-significant post-treatment improvement on the BRIEF (intention-to-treat: d = 0.27, p = .18; per protocol: d = 0.33, p = .11). Significantly more children showed reliable post-treatment improvement following MBI+CAU versus CAU-only (32% versus 11%, p < .05, Number-Needed-to-Treat = 4.7). ADHD symptoms significantly reduced post-treatment according to parent (Conners' and SWAN) and teacher ratings (BRIEF) per protocol. Only parent-rated hyperactivity impulsivity (SWAN) remained significantly reduced at 6-month follow-up. Post-treatment group differences on other secondary child outcomes were consistently favour of MBI+CAU, but mostly non-significant; no significant differences were found at follow-ups. Regarding parent outcomes, significant post-treatment improvements were found for their own ADHD symptoms, well-being and mindful parenting. At follow-ups, some significant effects remained (ADHD symptoms, mindful parenting), some additional significant effects appeared (other psychological symptoms, self-compassion) and others disappeared/remained non-significant. CONCLUSIONS: Family MBI+CAU did not outperform CAU-only in reducing child self-control deficits on a group level but more children reliably improved. Effects on parents were larger and more durable. When CAU for ADHD is insufficient, family MBI could be a valuable addition.

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.

Refinement by integration: aggregated effects of multimodal imaging markers on adult ADHD.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is biologically heterogeneous, with different biological predispositions - mediated through developmental processes - converging upon a common clinical phenotype. Brain imaging studies have variably shown altered brain structure, activity and connectivity in children and adults with ADHD. Recent methodological developments allow for the integration of information across imaging modalities, potentially yielding a more coherent view regarding the biology underlying the disorder. METHODS: We analyzed a sample of adults with persistent ADHD and healthy controls using an advanced multimodal linked independent component analysis approach. Diffusion and structural MRI data were fused to form imaging markers reflecting independent components that explain variation across modalities. We included these markers as predictors into logistic regression models on adult ADHD and put those into context with predictions of estimated intelligence, age and sex. RESULTS: We included 87 adults with ADHD and 93 controls in our analysis. Participants' courses associated with all imaging markers explained 27.86% of the variance in adult ADHD. No single imaging modality dominated this result. Instead, it was explained by aggregation of relatively small effects across several modalities and markers. One of the top markers for adult ADHD was multimodal and linked to morphological and microstructural effects within anterior temporal brain regions; another was linked to cortical thickness. Several markers were also influenced by estimated intelligence, age and/or sex. LIMITATIONS: Although complex analytical approaches, such as the one applied here, provide insight into otherwise hidden mechanisms, they also increase the complexity of interpretations. CONCLUSION: No dominant imaging modality or marker characterizes structural brain phenotypes in adults with ADHD, but we can refine our characterization of the disorder by the integration of small effects across modalities.

Five factor model personality traits relate to adult attention-deficit/hyperactivity disorder but not to their distinct neurocognitive profiles.

Deficits in multiple neuropsychological domains and specific personality profiles have been observed in attention-deficit/hyperactivity disorder (ADHD). In this study we investigated whether personality traits are related to neurocognitive profiles in adults with ADHD. Neuropsychological performance and Five Factor Model (FFM) personality traits were measured in adults with ADHD (n = 133) and healthy controls (n = 132). Three neuropsychological profiles, derived from previous community detection analyses, were investigated for personality trait differences. Irrespective of cognitive profile, participants with ADHD showed significantly higher Neuroticism and lower Extraversion, Agreeableness, and Conscientiousness than healthy controls. Only the FFM personality factor Openness differed significantly between the three profiles. Higher Openness was more common in those with aberrant attention and inhibition than those with increased delay discounting and atypical working memory / verbal fluency. The results suggest that the personality trait Openness, but not any other FFM factor, is linked to neurocognitive profiles in ADHD. ADHD symptoms rather than profiles of cognitive impairment have associations with personality traits.

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.

Brain imaging genetics in ADHD and beyond - Mapping pathways from gene to disorder at different levels of complexity.

Attention-deficit/hyperactivity disorder (ADHD) is a common and often persistent neurodevelopmental disorder. Beyond gene-finding, neurobiological parameters, such as brain structure, connectivity, and function, have been used to link genetic variation to ADHD symptomatology. We performed a systematic review of brain imaging genetics studies involving 62 ADHD candidate genes in childhood and adult ADHD cohorts. Fifty-one eligible research articles described studies of 13 ADHD candidate genes. Almost exclusively, single genetic variants were studied, mostly focussing on dopamine-related genes. While promising results have been reported, imaging genetics studies are thus far hampered by methodological differences in study design and analysis methodology, as well as limited sample sizes. Beyond reviewing imaging genetics studies, we also discuss the need for complementary approaches at multiple levels of biological complexity and emphasize the importance of combining and integrating findings across levels for a better understanding of biological pathways from gene to disease. These may include multi-modal imaging genetics studies, bioinformatic analyses, and functional analyses of cell and animal models.

Meta-analysis of the DRD5 VNTR in persistent ADHD.

Attention-Deficit/Hyperactivity Disorder (ADHD) is a common neuropsychiatric disorder with a complex genetic background. DRD5, the gene encoding the dopamine receptor D5, was recently confirmed as a candidate gene for ADHD in children through meta-analysis. In this study, we aimed at studying the association of the ADHD-associated variable number tandem repeat (VNTR) polymorphism upstream of DRD5 with adult ADHD. We compiled data from six sites of the International Multicentre persistent ADHD CollaboraTion (IMpACT) and reached N=6979 (3344 cases and 3635 healthy participants), the largest sample investigated so far. We tested the association of the common DRD5 alleles with categorically defined ADHD and with inattentive and hyperactive/impulsive symptom counts. Our findings provide evidence that none of the common DRD5 alleles are associated with ADHD risk or ADHD symptom counts in adults.

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.

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.