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.
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
Diffusion tensor imaging (DTI) allows in vivo examination of the microstructural integrity of white matter brain tissue. A systematic review and quantitative meta-analysis using GingerALE were ...undertaken to compare current DTI findings in patients with ADHD and healthy controls to further unravel the neurobiological underpinnings of the disorder. Online databases were searched for DTI studies comparing white matter integrity between ADHD patients and healthy controls. Fifteen studies met inclusion criteria. Alterations in white matter integrity were found in widespread areas, most consistently so in the right anterior corona radiata, right forceps minor, bilateral internal capsule, and left cerebellum, areas previously implicated in the pathophysiology of the disorder. Current literature is critically discussed in terms of its important methodological limitations and challenges, and guidelines for future DTI research are provided. While more research is needed, DTI proves to be a promising technique, providing new prospects and challenges for future research into the pathophysiology 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.
IMPORTANCE: Attention-deficit/hyperactivity disorder (ADHD) is a heritable neurodevelopmental disorder. It has been linked to reductions in total brain volume and subcortical abnormalities. However, ...owing to heterogeneity within and between studies and limited sample sizes, findings on the neuroanatomical substrates of ADHD have shown considerable variability. Moreover, it remains unclear whether neuroanatomical alterations linked to ADHD are also present in the unaffected siblings of those with ADHD. OBJECTIVE: To examine whether ADHD is linked to alterations in whole-brain and subcortical volumes and to study familial underpinnings of brain volumetric alterations in ADHD. DESIGN, SETTING, AND PARTICIPANTS: In this cross-sectional study, we included participants from the large and carefully phenotyped Dutch NeuroIMAGE sample (collected from September 2009-December 2012) consisting of 307 participants with ADHD, 169 of their unaffected siblings, and 196 typically developing control individuals (mean age, 17.21 years; age range, 8-30 years). MAIN OUTCOMES AND MEASURES: Whole-brain volumes (total brain and gray and white matter volumes) and volumes of subcortical regions (nucleus accumbens, amygdala, caudate nucleus, globus pallidus, hippocampus, putamen, thalamus, and brainstem) were derived from structural magnetic resonance imaging scans using automated tissue segmentation. RESULTS: Regression analyses revealed that relative to control individuals, participants with ADHD had a 2.5% smaller total brain (β = −31.92; 95% CI, −52.69 to −11.16; P = .0027) and a 3% smaller total gray matter volume (β = −22.51; 95% CI, −35.07 to −9.96; P = .0005), while total white matter volume was unaltered (β = −10.10; 95% CI, −20.73 to 0.53; P = .06). Unaffected siblings had total brain and total gray matter volumes intermediate to participants with ADHD and control individuals. Significant age-by-diagnosis interactions showed that older age was linked to smaller caudate (P < .001) and putamen (P = .01) volumes (both corrected for total brain volume) in control individuals, whereas age was unrelated to these volumes in participants with ADHD and their unaffected siblings. Attention-deficit/hyperactivity disorder was not significantly related to the other subcortical volumes. CONCLUSIONS AND RELEVANCE: Global differences in gray matter volume may be due to alterations in the general mechanisms underlying normal brain development in ADHD. The age-by-diagnosis interaction in the caudate and putamen supports the relevance of different brain developmental trajectories in participants with ADHD vs control individuals and supports the role of subcortical basal ganglia alterations in the pathophysiology of ADHD. Alterations in total gray matter and caudate and putamen volumes in unaffected siblings suggest that these volumes are linked to familial risk for ADHD.
•Explored how scanning settings affect the image pattern in multi-site sMRI studies.•A data-driven SBM correction was designed and tested.•Consistent field strength, sequence design and RF coil are ...strongly recommended.•SBM proves a flexible and effective approach to detect and clean scanning effects.
Pooling of multi-site MRI data is often necessary when a large cohort is desired. However, different scanning platforms can introduce systematic differences which confound true effects of interest. One may reduce multi-site bias by calibrating pivotal scanning parameters, or include them as covariates to improve the data integrity.
In the present study we use a source-based morphometry (SBM) model to explore scanning effects in multi-site sMRI studies and develop a data-driven correction. Specifically, independent components are extracted from the data and investigated for associations with scanning parameters to assess the influence. The identified scanning-related components can be eliminated from the original data for correction.
A small set of SBM components captured most of the variance associated with the scanning differences. In a dataset of 1460 healthy subjects, pronounced and independent scanning effects were observed in brainstem and thalamus, associated with magnetic field strength-inversion time and RF-receiving coil. A second study with 110 schizophrenia patients and 124 healthy controls demonstrated that scanning effects can be effectively corrected with the SBM approach.
Both SBM and GLM correction appeared to effectively eliminate the scanning effects. Meanwhile, the SBM-corrected data yielded a more significant patient versus control group difference and less questionable findings.
It is important to calibrate scanning settings and completely examine individual parameters for the control of confounding effects in multi-site sMRI studies. Both GLM and SBM correction can reduce scanning effects, though SBM's data-driven nature provides additional flexibility and is better able to handle collinear effects.
The left and right sides of the human brain are specialized for different kinds of information processing, and much of our cognition is lateralized to an extent toward one side or the other. ...Handedness is a reflection of nervous system lateralization. Roughly ten percent of people are mixed- or left-handed, and they show an elevated rate of reductions or reversals of some cerebral functional asymmetries compared to right-handers. Brain anatomical correlates of left-handedness have also been suggested. However, the relationships of left-handedness to brain structure and function remain far from clear. We carried out a comprehensive analysis of cortical surface area differences between 106 left-handed subjects and 1960 right-handed subjects, measured using an automated method of regional parcellation (FreeSurfer, Destrieux atlas). This is the largest study sample that has so far been used in relation to this issue. No individual cortical region showed an association with left-handedness that survived statistical correction for multiple testing, although there was a nominally significant association with the surface area of a previously implicated region: the left precentral sulcus. Identifying brain structural correlates of handedness may prove useful for genetic studies of cerebral asymmetries, as well as providing new avenues for the study of relations between handedness, cerebral lateralization and cognition.
Gait disturbances are common in the elderly. Cerebral small vessel disease, including white matter lesions and lacunars infarcts, is thought to disrupt white matter tracts that connect important ...motor regions, hence resulting in gait disturbances. Pathological studies have demonstrated abnormalities in white matter that may appear normal on brain imaging. The loss of integrity in such normal-appearing white matter may partly be due to small vessel disease and may play a role in causing gait disturbances. The white matter regions involved in these gait disturbances, both in white matter lesions and normal-appearing white matter, remain unclear. We, therefore, aimed to investigate the relation between the location of white matter lesions and gait using voxel-based morphometry analysis, as well as between white matter integrity and gait by applying tract-based spatial statistics to diffusion tensor imaging parameters. Magnetic resonance imaging was carried out on 429 individuals in the age range of 50 and 85 years, with cerebral small vessel disease without dementia or parkinsonism. Gait was assessed quantitatively. White matter lesions, especially in the centrum semiovale and periventricular frontal lobe, were related to a lower gait velocity, shorter stride length and broader stride width. Loss of white matter integrity, as indicated by a lower fractional anisotropy and higher mean diffusivity, in numerous regions was related to a lower gait performance. Most of these regions were located in the normal-appearing white matter. The strongest significant association was found in the corpus callosum, particularly the genu. Most of the associations in the normal-appearing white matter disappeared after controlling for white matter lesions and lacunar infarcts, except for some in the corpus callosum. In conclusion, our study showed that using a combination of voxel-based morphometry analysis of the white matter lesions and diffusion tensor imaging is of added value in investigating the pathophysiology of gait disturbances in subjects with small vessel disease. Our data demonstrate that, in elderly subjects with small vessel disease, widespread disruption of white matter integrity, predominantly in the normal-appearing white matter, is involved in gait disturbances. In particular, loss of fibres interconnecting bilateral cortical regions, especially the prefrontal cortex that is involved in cognitive control on motor performance, may be important. The most important mechanisms underlying affected normal-appearing white matter are probably a direct effect of small vessel disease or, indirectly, remote effects of white matter lesions and lacunar infarcts.
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.
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.
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).
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.
National Institutes of Health.
Attention-deficit/hyperactivity disorder (ADHD) is a heritable neuropsychiatric disorder associated with abnormal reward processing. Limited and inconsistent data exist about the neural mechanisms ...underlying this abnormality. Furthermore, it is not known whether reward processing is abnormal in unaffected siblings of participants with ADHD.
We used event-related functional magnetic resonance imaging (fMRI) to investigate brain responses during reward anticipation and receipt with an adapted monetary incentive delay task in a large sample of adolescents and young adults with ADHD (n = 150), their unaffected siblings (n = 92), and control participants (n = 108), all of the same age.
Participants with ADHD showed, relative to control participants, increased responses in the anterior cingulate, anterior frontal cortex, and cerebellum during reward anticipation, and in the orbitofrontal, occipital cortex and ventral striatum. Responses of unaffected siblings were increased in these regions as well, except for the cerebellum during anticipation and ventral striatum during receipt.
ADHD in adolescents and young adults is associated with enhanced neural responses in frontostriatal circuitry to anticipation and receipt of reward. The findings support models emphasizing aberrant reward processing in ADHD, and suggest that processing of reward is subject to familial influences. Future studies using standard monetary incentive delay task parameters are needed to replicate our findings.
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