Cognitive Functioning in Long-Term Benzodiazepine Users.

BACKGROUND: Benzodiazepines are widely used in the treatment of anxiety disorders and sleep disturbances, but negative cognitive side effects have been reported after long-term use. Studies on the cognitive effects of long-term benzodiazepine use to date have typically included small samples and limited cognitive assessments. OBJECTIVES: This study examined cognitive performance on four cognitive domains in long-term benzodiazepine users, compared to normative data. Furthermore, it was examined whether sex, age, benzodiazepine dose, and state and trait anxiety moderated cognitive functioning in long-term benzodiazepine users. METHODS: Neuropsychological tests targeting different cognitive domains were administered to 92 patients with long-term benzodiazepine use who were accepted for enrolment into a benzodiazepine discontinuation programme in an academic hospital. Test scores were compared to a large normative data sample. RESULTS: Of the long-term benzodiazepine users, 20.7% could be classified as cognitively impaired across all domains, with the largest effects found in the domains processing speed and sustained attention, and an overall worse performance in women, an effect which appears to be moderated by state anxiety. No effects of age or benzodiazepine dose were found. CONCLUSIONS: These results extend those of earlier studies on benzodiazepine effects on specific cognitive domains. This study implies an overall detrimental cognitive effect in long-term benzodiazepine users rather than specific effects. Therefore, long-term benzodiazepine use should be avoided, and once present, tailored interventions aimed at tapering benzodiazepines are warranted.

Differences in functional brain organization during gesture recognition between autistic and neurotypical individuals.

Persons with and without autism process sensory information differently. Differences in sensory processing are directly relevant to social functioning and communicative abilities, which are known to be hampered in persons with autism. We collected functional magnetic resonance imaging data from 25 autistic individuals and 25 neurotypical individuals while they performed a silent gesture recognition task. We exploited brain network topology, a holistic quantification of how networks within the brain are organized to provide new insights into how visual communicative signals are processed in autistic and neurotypical individuals. Performing graph theoretical analysis, we calculated two network properties of the action observation network: 'local efficiency', as a measure of network segregation, and 'global efficiency', as a measure of network integration. We found that persons with autism and neurotypical persons differ in how the action observation network is organized. Persons with autism utilize a more clustered, local-processing-oriented network configuration (i.e. higher local efficiency) rather than the more integrative network organization seen in neurotypicals (i.e. higher global efficiency). These results shed new light on the complex interplay between social and sensory processing in autism.

Translation, Cross-Cultural Adaptation, and Validation of a Dutch Version of the Actions and Feelings Questionnaire in Autistic and Neurotypical Adults.

The actions and feelings questionnaire (AFQ) provides a short, self-report measure of how well someone uses and understands visual communicative signals such as gestures. The objective of this study was to translate and cross-culturally adapt the AFQ into Dutch (AFQ-NL) and validate this new version in neurotypical and autistic populations. Translation and adaptation of the AFQ consisted of forward translation, synthesis, back translation, and expert review. In order to validate the AFQ-NL, we assessed convergent and divergent validity. We additionally assessed internal consistency using Cronbach's alpha. Validation and reliability outcomes were all satisfactory. The AFQ-NL is a valid adaptation that can be used for both autistic and neurotypical populations in the Netherlands.

Differences in the production and perception of communicative kinematics in autism.

In human communication, social intentions and meaning are often revealed in the way we move. In this study, we investigate the flexibility of human communication in terms of kinematic modulation in a clinical population, namely, autistic individuals. The aim of this study was twofold: to assess (a) whether communicatively relevant kinematic features of gestures differ between autistic and neurotypical individuals, and (b) if autistic individuals use communicative kinematic modulation to support gesture recognition. We tested autistic and neurotypical individuals on a silent gesture production task and a gesture comprehension task. We measured movement during the gesture production task using a Kinect motion tracking device in order to determine if autistic individuals differed from neurotypical individuals in their gesture kinematics. For the gesture comprehension task, we assessed whether autistic individuals used communicatively relevant kinematic cues to support recognition. This was done by using stick-light figures as stimuli and testing for a correlation between the kinematics of these videos and recognition performance. We found that (a) silent gestures produced by autistic and neurotypical individuals differ in communicatively relevant kinematic features, such as the number of meaningful holds between movements, and (b) while autistic individuals are overall unimpaired at recognizing gestures, they processed repetition and complexity, measured as the amount of submovements perceived, differently than neurotypicals do. These findings highlight how subtle aspects of neurotypical behavior can be experienced differently by autistic individuals. They further demonstrate the relationship between movement kinematics and social interaction in high-functioning autistic individuals. LAY SUMMARY: Hand gestures are an important part of how we communicate, and the way that we move when gesturing can influence how easy a gesture is to understand. We studied how autistic and typical individuals produce and recognize hand gestures, and how this relates to movement characteristics. We found that autistic individuals moved differently when gesturing compared to typical individuals. In addition, while autistic individuals were not worse at recognizing gestures, they differed from typical individuals in how they interpreted certain movement characteristics.

Is a Negative Attentional Bias in Individuals with Autism Spectrum Disorder Explained by Comorbid Depression? An Eye-Tracking Study.

Heightened attention towards negative information is characteristic of depression. Evidence is emerging for a negative attentional bias in Autism spectrum disorder (ASD), perhaps driven by the high comorbidity between ASD and depression. We investigated whether ASD is characterised by a negative attentional bias and whether this can be explained by comorbid (sub) clinical depression. Participants (n = 116) with current (CD) or remitted depression (RD) and/or ASD, and 64 controls viewed positively and negatively valenced (non-)social pictures. Groups were compared on three components of visual attention using linear mixed models. Both CD individuals with and without ASD, but not remitted depressed and never-depressed ASD individuals showed a negative bias, suggesting that negative attentional bias might be a depressive state-specific marker for depression in ASD.

Mindfulness-based cognitive therapy v. treatment as usual in adults with ADHD: a multicentre, single-blind, randomised controlled trial.

BACKGROUND: There is a high need for evidence-based psychosocial treatments for adult attention-deficit hyperactivity disorder (ADHD) to offer alongside treatment as usual (TAU). Mindfulness-based cognitive therapy (MBCT) is a promising psychosocial treatment. This trial investigated the efficacy of MBCT + TAU v. TAU in reducing core symptoms in adults with ADHD. METHODS: A multicentre, single-blind, randomised controlled trial (ClinicalTrials.gov: NCT02463396). Participants were randomly assigned to MBCT + TAU (n = 60), an 8-weekly group therapy including meditation exercises, psychoeducation and group discussions, or TAU only (n = 60), which reflected usual treatment in the Netherlands and included pharmacotherapy and/or psychoeducation. Primary outcome was ADHD symptoms rated by blinded clinicians. Secondary outcomes included self-reported ADHD symptoms, executive functioning, mindfulness skills, self-compassion, positive mental health and general functioning. Outcomes were assessed at baseline, post-treatment, 3- and 6-month follow-up. Post-treatment effects at group and individual level, and follow-up effects were examined. RESULTS: In MBCT + TAU patients, a significant reduction of clinician-rated ADHD symptoms was found at post-treatment [M difference = -3.44 (-5.75, -1.11), p = 0.004, d = 0.41]. This effect was maintained until 6-month follow-up. More MBCT + TAU (27%) than TAU participants (4%) showed a ⩾30% reduction of ADHD symptoms (p = 0.001). MBCT + TAU patients compared with TAU patients also reported significant improvements in ADHD symptoms, mindfulness skills, self-compassion and positive mental health at post-treatment, which were maintained until 6-month follow-up. Although patients in MBCT + TAU compared with TAU reported no improvement in executive functioning at post-treatment, they did report improvement at 6-month follow-up. CONCLUSIONS: MBCT might be a valuable treatment option alongside TAU for adult ADHD aimed at alleviating symptoms.

The Efficacy of Adapted MBCT on Core Symptoms and Executive Functioning in Adults With ADHD: A Preliminary Randomized Controlled Trial.

OBJECTIVE: The aim of this study was to examine the effectiveness of mindfulness as a treatment for adults diagnosed with ADHD. A 12-week-adapted mindfulness-based cognitive therapy (MBCT) program is compared with a waiting list (WL) group. METHOD: Adults with ADHD were randomly allocated to MBCT ( n = 55) or waitlist ( n = 48). Outcome measures included investigator-rated ADHD symptoms (primary), self-reported ADHD symptoms, executive functioning, depressive and anxiety symptoms, patient functioning, and mindfulness skills. RESULTS: MBCT resulted in a significant reduction of ADHD symptoms, both investigator-rated and self-reported, based on per-protocol and intention-to-treat analyses. Significant improvements in executive functioning and mindfulness skills were found. Additional analyses suggested that the efficacy of MBCT in reducing ADHD symptoms and improving executive functioning is partially mediated by an increase in the mindfulness skill "Act With Awareness." No improvements were observed for depressive and anxiety symptoms, and patient functioning. CONCLUSION: This study provides preliminary support for the effectiveness of MBCT for adults with ADHD.

High Functioning Autism Spectrum Disorders in Adults: Consequences for Primary Caregivers Compared to Schizophrenia and Depression.

Primary caregivers experience consequences from being in close contact to a person with autism spectrum disorder (ASD). This study used the Involvement Evaluation Questionnaire to explore the level of consequences of 104 caregivers involved with adults with High Functioning ASD (HF-ASD) and compared these with the consequences reported by caregivers of patients suffering from depression and schizophrenia. Caregivers involved with adults with an HF-ASD experience overall consequences comparable to those involved with patients with depression or schizophrenia. Worrying was the most reported consequence. More tension was experienced by the caregivers of ASD patients, especially by spouses. More care and attention for spouses of adults with an HF-ASD appears to be needed.

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.

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.

fMRI Neurofeedback Training for Increasing Anterior Cingulate Cortex Activation in Adult Attention Deficit Hyperactivity Disorder. An Exploratory Randomized, Single-Blinded Study.

Attention Deficit Hyperactivity Disorder (ADHD) is characterized by poor cognitive control/attention and hypofunctioning of the dorsal anterior cingulate cortex (dACC). In the current study, we investigated for the first time whether real-time fMRI neurofeedback (rt-fMRI) training targeted at increasing activation levels within dACC in adults with ADHD leads to a reduction of clinical symptoms and improved cognitive functioning. An exploratory randomized controlled treatment study with blinding of the participants was conducted. Participants with ADHD (n = 7 in the neurofeedback group, and n = 6 in the control group) attended four weekly MRI training sessions (60-min training time/session), during which they performed a mental calculation task at varying levels of difficulty, in order to learn how to up-regulate dACC activation. Only neurofeedback participants received continuous feedback information on actual brain activation levels within dACC. Before and after the training, ADHD symptoms and relevant cognitive functioning was assessed. Results showed that both groups achieved a significant increase in dACC activation levels over sessions. While there was no significant difference between the neurofeedback and control group in clinical outcome, neurofeedback participants showed stronger improvement on cognitive functioning. The current study demonstrates the general feasibility of the suggested rt-fMRI neurofeedback training approach as a potential novel treatment option for ADHD patients. Due to the study's small sample size, potential clinical benefits need to be further investigated in future studies. TRIAL REGISTRATION: ISRCTN12390961.

Relationships Between Functional Outcomes and Symptomatic Improvement in Atomoxetine-Treated Adult Patients with Attention-Deficit/Hyperactivity Disorder: Post Hoc Analysis of an Integrated Database.

BACKGROUND: Atomoxetine treatment is associated with improvements in functional outcomes in patients with attention-deficit/hyperactivity disorder (ADHD), although relationships between improvements in these outcomes and reductions in ADHD symptoms have not been comprehensively investigated in adults. OBJECTIVES: The aim of this study was to assess relationships between functional outcomes and ADHD symptoms (primary objective), and to assess time courses of changes in functional outcomes from baseline to weeks 10 and 24 (secondary objective). METHODS: We analyzed data pooled from seven Eli Lilly-sponsored placebo-controlled trials of atomoxetine in adults with ADHD that had Conners' Adult ADHD Rating Scales-Investigator Rated: Screening Version (CAARS-Inv:SV) total scores and functional outcome data at baseline and at week 10. Two trials also had these data at week 24. Patients were included in these pooled analyses if they had a CAARS-Inv:SV total score at baseline and at one or more post-baseline visits at weeks 10 or 24, or had post-baseline scores that would allow missing scores at weeks 10 or 24 to be imputed. To address the primary objective, changes in functional outcomes during treatment with atomoxetine versus placebo were assessed using last observation carried forward (LOCF) analysis of covariance (ANCOVA) and mixed-effects model repeated measures (MMRM) analysis, and correlations between score changes in CAARS-Inv:SV total and functional outcomes were assessed using Spearman's rank correlation coefficient (r) at weeks 10 and 24. The secondary objective was addressed using MMRM. RESULTS: At baseline, patients generally had moderately severe or worse ADHD symptoms (based on CAARS-Inv:SV total scores) and impaired functional outcomes (based on Adult ADHD Quality-of-Life [AAQoL], Behavior Rating Inventory of Executive Function-Adult Version [BRIEF-A], Sheehan Disability Scale [SDS], and 36-item Short-Form Health Survey [SF-36] scores). These baseline characteristics were comparable in the atomoxetine and placebo groups. For atomoxetine versus placebo, statistically significant improvements were detected in AAQoL total and subscores at weeks 10 and 24, and in BRIEF-A Self-Report scores at week 10, but not in BRIEF-A Informant Report or SDS scores at week 10 (no BRIEF-A or SDS data were available at week 24), and not in SF-36 at weeks 10 or 24. All functional improvements were gradual. During treatment with atomoxetine, there were moderate correlations between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.58 to -0.39; n = 394-545), and also with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 256). With placebo, moderate correlations were also found between reductions in CAARS-Inv:SV total scores and increases in AAQoL total and subscores at weeks 10 and 24 (r range -0.56 to -0.28; n = 321-542), and with reductions in BRIEF-A Self-Report at week 10 (r = 0.49; n = 271). However, correlations between changes in CAARS-Inv:SV and BRIEF-A Informant at week 10 were low for atomoxetine-treated patients (r = 0.25; n = 65), moderate with placebo (r = 0.42; n = 72), and there were low/no correlations between changes in CAARS-Inv:SV and functional outcome rating scales that are not specific to ADHD; that is, for atomoxetine-treated patients, SDS total r = 0.19 (n = 32 at week 10) and SF-36 r range - 0.20 to -0.01 (n = 51 at week 10, n = 183 at week 24). CONCLUSIONS: Atomoxetine-treated adult patients experienced improvements in functional outcomes (AAQoL and BRIEF-A Self-Report) that correlated with reductions in ADHD symptoms. Although atomoxetine improved both the ADHD symptoms and functional outcomes, the correlation between symptoms and functional outcomes was low to moderate, suggesting that they measure overlapping but different aspects of the disorder. Hence, clinicians should assess not just ADHD symptoms, but also the functional impairments.

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.

Mindfulness based cognitive therapy versus treatment as usual in adults with attention deficit hyperactivity disorder (ADHD).

BACKGROUND: Adults with attention deficit hyperactivity disorder (ADHD) often present with a lifelong pattern of core symptoms that is associated with impairments of functioning in daily life. This has a substantial personal and economic impact. In clinical practice there is a high need for additional or alternative interventions for existing treatments, usually consisting of pharmacotherapy and/or psycho-education. Although previous studies show preliminary evidence for the effectiveness of mindfulness-based interventions in reducing ADHD symptoms and improving executive functioning, these studies have methodological limitations. This study will take account of these limitations and will examine the effectiveness of Mindfulness Based Cognitive Therapy (MBCT) in further detail. METHODS/DESIGN: A multi-centre, parallel-group, randomised controlled trial will be conducted in N = 120 adults with ADHD. Patients will be randomised to MBCT in addition to treatment as usual (TAU) or TAU alone. Assessments will take place at baseline and at three, six and nine months after baseline. Primary outcome measure will be severity of ADHD symptoms rated by a blinded clinician. Secondary outcome measures will be self-reported ADHD symptoms, executive functioning, mindfulness skills, self-compassion, positive mental health and general functioning. In addition, a cost-effectiveness analysis will be conducted. DISCUSSION: This trial will offer valuable information about the clinical and cost-effectiveness of MBCT in addition to TAU compared to TAU alone in adults swith ADHD. TRIAL REGISTRATION: ClinicalTrials.gov NCT02463396. Registered 8 June 2015.

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.

Case-control genome-wide association study of persistent attention-deficit hyperactivity disorder identifies FBXO33 as a novel susceptibility gene for the disorder.

Attention-deficit hyperactivity disorder (ADHD) is a neurodevelopmental disorder with high heritability. At least 30% of patients diagnosed in childhood continue to suffer from ADHD during adulthood and genetic risk factors may play an essential role in the persistence of the disorder throughout lifespan. To date, genome-wide association studies (GWAS) of ADHD have been completed in seven independent datasets, six of which were pediatric samples and one on persistent ADHD using a DNA-pooling strategy, but none of them reported genome-wide significant associations. In an attempt to unravel novel genes for the persistence of ADHD into adulthood, we conducted the first two-stage GWAS in adults with ADHD. The discovery sample included 607 ADHD cases and 584 controls. Top signals were subsequently tested for replication in three independent follow-up samples of 2104 ADHD patients and 1901 controls. None of the findings exceeded the genome-wide threshold for significance (PGC<5e-08), but we found evidence for the involvement of the FBXO33 (F-box only protein 33) gene in combined ADHD in the discovery sample (P=9.02e-07) and in the joint analysis of both stages (P=9.7e-03). Additional evidence for a FBXO33 role in ADHD was found through gene-wise and pathway enrichment analyses in our genomic study. Risk alleles were associated with lower FBXO33 expression in lymphoblastoid cell lines and with reduced frontal gray matter volume in a sample of 1300 adult subjects. Our findings point for the first time at the ubiquitination machinery as a new disease mechanism for adult ADHD and establish a rationale for searching for additional risk variants in ubiquitination-related genes.