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Microorganisms in the human intestine (i.e. the gut microbiome) have an increasingly recognized impact on human health, including brain functioning. Attention-deficit/hyperactivity disorder (ADHD) is a neurodevelopmental disorder associated with abnormalities in dopamine neurotransmission and deficits in reward processing and its underlying neuro-circuitry including the ventral striatum. The microbiome might contribute to ADHD etiology via the gut-brain axis. In this pilot study, we investigated potential differences in the microbiome between ADHD cases and undiagnosed controls, as well as its relation to neural reward processing. We used 16S rRNA marker gene sequencing (16S) to identify bacterial taxa and their predicted gene functions in 19 ADHD and 77 control participants. Using functional magnetic resonance imaging (fMRI), we interrogated the effect of observed microbiome differences in neural reward responses in a subset of 28 participants, independent of diagnosis. For the first time, we describe gut microbial makeup of adolescents and adults diagnosed with ADHD. We found that the relative abundance of several bacterial taxa differed between cases and controls, albeit marginally significant. A nominal increase in the Bifidobacterium genus was observed in ADHD cases. In a hypothesis-driven approach, we found that the observed increase was linked to significantly enhanced 16S-based predicted bacterial gene functionality encoding cyclohexadienyl dehydratase in cases relative to controls. This enzyme is involved in the synthesis of phenylalanine, a precursor of dopamine. Increased relative abundance of this functionality was significantly associated with decreased ventral striatal fMRI responses during reward anticipation, independent of ADHD diagnosis and age. Our results show increases in gut microbiome predicted function of dopamine precursor synthesis between ADHD cases and controls. This increase in microbiome function relates to decreased neural responses to reward anticipation. Decreased neural reward anticipation constitutes one of the hallmarks of ADHD.

To understand the neurocognitive mechanisms that underlie heterogeneity in cognitive ageing, recent scientific efforts have led to a growing public availability of imaging cohort data. The Advanced BRain Imaging on ageing and Memory (ABRIM) project aims to add to these existing datasets by taking an adult lifespan approach to provide a cross-sectional, normative database with a particular focus on connectivity, myelinization and iron content of the brain in concurrence with cognitive functioning, mechanisms of reserve, and sleep-wake rhythms. ABRIM freely shares MRI and behavioural data from 295 participants between 18–80 years, stratified by age decade and sex (median age 52, IQR 36–66, 53.20% females). The ABRIM MRI collection consists of both the raw and pre-processed structural and functional MRI data to facilitate data usage among both expert and non-expert users. The ABRIM behavioural collection includes measures of cognitive functioning (i.e., global cognition, processing speed, executive functions, and memory), proxy measures of cognitive reserve (e.g., educational attainment, verbal intelligence, and occupational complexity), and various self-reported questionnaires (e.g., on depressive symptoms, pain, and the use of memory strategies in daily life and during a memory task). In a sub-sample ( n = 120), we recorded sleep-wake rhythms using an actigraphy device (Actiwatch 2, Philips Respironics) for a period of 7 consecutive days. Here, we provide an in-depth description of our study protocol, pre-processing pipelines, and data availability. ABRIM provides a cross-sectional database on healthy participants throughout the adult lifespan, including numerous parameters relevant to improve our understanding of cognitive ageing. Therefore, ABRIM enables researchers to model the advanced imaging parameters and cognitive topologies as a function of age, identify the normal range of values of such parameters, and to further investigate the diverse mechanisms of reserve and resilience.

Research into the effect of nutrition on attention-deficit hyperactivity disorder (ADHD) in children has shown that the few-foods diet (FFD) substantially decreases ADHD symptoms in 60% of children. However, the underlying mechanism is unknown. In this open-label nutritional intervention study we investigated whether behavioural changes after following an FFD are associated with changes in brain function during inhibitory control in 79 boys with ADHD, aged 8–10 years. Parents completed the ADHD Rating Scale before (t1) and after the FFD (t2). Functional magnetic resonance imaging (fMRI) scans were acquired during a stop-signal task at t1 and t2, and initial subject-level analyses were done blinded for ARS scores. Fifty (63%) participants were diet responders, showing a decrease of ADHD symptoms of at least 40%. Fifty-three children had fMRI scans of sufficient quality for further analysis. Region-of-interest analyses demonstrated that brain activation in regions implicated in the stop-signal task was not associated with ADHD symptom change. However, whole-brain analyses revealed a correlation between ADHD symptom decrease and increased precuneus activation (p FWE(cluster)  = 0.015 for StopSuccess > Go trials and p FWE(cluster)  < 0.001 for StopSuccess > StopFail trials). These results provide evidence for a neurocognitive mechanism underlying the efficacy of a few-foods diet in children with 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.

Motion artefacts are an important but often disregarded problem in diffusion-weighted imaging, which can readily lead to corrupt diffusion model estimations. The new processing method proposed in this paper uses robust tensor estimation that is spatially informed to efficiently detect the most frequently occurring artefacts, namely those that result from head and cardiac motion. Simulations demonstrate that the method is more robust and accurate than previous methods. The tensor estimates are more accurate in motion artefact-free conditions, less sensitive to increases in artefact magnitude and more resistant to increasing artefact frequency. Evaluation with real diffusion-weighted (DW) imaging data shows that the method works excellently, even for datasets with a high degree of motion that otherwise need to be discarded. The method is not limited to diffusion tensor imaging but also yields objective artefact reflecting weights that can be used to inform subsequent processing or estimation of higher-order diffusion models. ►Motion artefacts are often disregarded but can corrupt diffusion tensor estimation ►PATCH uses robust estimation that exploits the spatial correlation of the artefacts ►PATCH is more robust, sensitive and accurate than previous methods ►PATCH provides weights that can inform the estimation of HARDI models

Background Cerebral small vessel disease (SVD) is a frequent finding on CT and MRI scans of elderly people and is related to vascular risk factors and cognitive and motor impairment, ultimately leading to dementia or parkinsonism in some. In general, the relations are weak, and not all subjects with SVD become demented or get parkinsonism. This might be explained by the diversity of underlying pathology of both white matter lesions (WML) and the normal appearing white matter (NAWM). Both cannot be properly appreciated with conventional MRI. Diffusion tensor imaging (DTI) provides alternative information on microstructural white matter integrity. The association between SVD, its microstructural integrity, and incident dementia and parkinsonism has never been investigated. Methods/Design The RUN DMC study is a prospective cohort study on the risk factors and cognitive and motor consequences of brain changes among 503 non-demented elderly, aged between 50-85 years, with cerebral SVD. First follow up is being prepared for July 2011. Participants alive will be included and invited to the research centre to undergo a structured questionnaire on demographics and vascular risk factors, and a cognitive, and motor, assessment, followed by a MRI protocol including conventional MRI, DTI and resting state fMRI. Discussion The follow up of the RUN DMC study has the potential to further unravel the causes and possibly better predict the consequences of changes in white matter integrity in elderly with SVD by using relatively new imaging techniques. When proven, these changes might function as a surrogate endpoint for cognitive and motor function in future therapeutic trials. Our data could furthermore provide a better understanding of the pathophysiology of cognitive and motor disturbances in elderly with SVD. The execution and completion of the follow up of our study might ultimately unravel the role of SVD on the microstructural integrity of the white matter in the transition from \"normal\" aging to cognitive and motor decline and impairment and eventually to incident dementia and parkinsonism.

Recent studies have reported abnormal functional connectivity patterns in the brains of people with autism that may be accompanied by decreases in white matter integrity. Since autism is a developmental disorder, we aim to investigate the nature and location of decreases in white and grey matter integrity in an adolescent sample while accounting for age. We used structural (T1) imaging to study brain volumetrics and diffusion tensor imaging (DTI) to investigate white and grey matter integrity in people with autism. We obtained magnetic resonance images for adolescents aged 12–18 years with high-functioning autism and from matched controls. Fractional anisotropy and mean diffusivity, as well as grey and white matter volumetrics were analyzed. There were 17 participants with autism and 25 matched controls included in this study. Participants with autism had lower fractional anisotropy in the left and right superior and inferior longitudinal fasciculus, but this effect was not significant after adjusting for age and intelligence quotient (IQ). The kurtosis of the white matter fractional anisotropy probability distribution was higher in this participant group, with and without adjustment for age and IQ. Most notably, however, the mean diffusivity levels were markedly increased in the autism group throughout the brain, and the mean diffusivity probability distributions of both grey and white matter were shifted toward a higher value, particularly with age and IQ adjustment. No volumetric differences in grey and white matter were found. We corrected for age and IQ using a linear model. The study was also limited by its sample size, investigated age range and cross-sectional design. The findings suggest that autism is characterized by a generalized reduction of white matter integrity that is associated with an increase of interstitial space. The generalized manifestation of the white matter abnormalities provides an important new perspective on autism as a connectivity disorder.

Copy number variants (CNVs) at the Breakpoint 1 to Breakpoint 2 region at 15q11.2 (BP1-2) are associated with language-related difficulties and increased risk for developmental disorders in which language is compromised. Towards underlying mechanisms, we investigated relationships between single nucleotide polymorphisms (SNPs) across the region and quantitative measures of human brain structure obtained by magnetic resonance imaging of healthy subjects. We report an association between rs4778298, a common variant at CYFIP1, and inter-individual variation in surface area across the left supramarginal gyrus (lh.SMG), a cortical structure implicated in speech and language in independent discovery (n = 100) and validation cohorts (n = 2621). In silico analyses determined that this same variant, and others nearby, is also associated with differences in levels of CYFIP1 mRNA in human brain. One of these nearby polymorphisms is predicted to disrupt a consensus binding site for FOXP2, a transcription factor implicated in speech and language. Consistent with a model where FOXP2 regulates CYFIP1 levels and in turn influences lh.SMG surface area, analysis of publically available expression data identified a relationship between expression of FOXP2 and CYFIP1 mRNA in human brain. We propose that altered CYFIP1 dosage, through aberrant patterning of the lh.SMG, may contribute to language-related difficulties associated with BP1-2 CNVs. More generally, this approach may be useful in clarifying the contribution of individual genes at CNV risk loci.

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. 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. 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. 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. This study suggests that reduced microstructural integrity of the right SLF is associated with elevated τ in patients with ADHD.

The perceptual pattern in autism has been related to either a specific localized processing deficit or a pathway-independent, complexity-specific anomaly. We examined auditory perception in autism using an auditory disembedding task that required spectral and temporal integration. 23 children with high-functioning-autism and 23 matched controls participated. Participants were presented with two-syllable words embedded in various auditory backgrounds (pink noise, moving ripple, amplitude-modulated pink noise, amplitude-modulated moving ripple) to assess speech-in-noise-reception thresholds. The gain in signal perception of pink noise with temporal dips relative to pink noise without temporal dips was smaller in children with autism ( p  = 0.008). Thus, the autism group was less able to integrate auditory information present in temporal dips in background sound, supporting the complexity-specific perceptual account.