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Abstract The association between Attention Deficit Hyperactivity Disorder (ADHD) and low-grade inflammation has been explored in children but rarely in adults. Inflammation is characteristic of some, but not all, patients with ADHD and might be influenced by ADHD medication but also lifestyle factors including nutrition, smoking, and stress. It is also still unclear if any specific symptoms are related to inflammation. Therefore, we assessed 96 inflammatory proteins in a deeply phenotyped cohort of 126 adult ADHD participants with a stable medication status using OLINK technology. A data-based, unsupervised hierarchical clustering method could identify two distinct biotypes within the 126 ADHD participants based on their inflammatory profile: a higher inflammatory potential (HIP) and a lower inflammatory protein potential (LIP) group. Biological processes that differed strongest between groups were related to the NF-κB pathway, chemokine signaling, IL-17 signaling, metabolic alterations, and chemokine attraction. A comparison of sample characteristics revealed that the HIP group was more likely to have higher levels of chronic stress (p

BackgroundAttention-deficit/hyperactivity disorder (ADHD) is a prevalent neurodevelopmental disorder. Neuroanatomic heterogeneity limits our understanding of ADHD's etiology. This study aimed to parse heterogeneity of ADHD and to determine whether patient subgroups could be discerned based on subcortical brain volumes.MethodsUsing the large ENIGMA-ADHD Working Group dataset, four subsamples of 993 boys with and without ADHD and to subsamples of 653 adult men, 400 girls, and 447 women were included in analyses. We applied exploratory factor analysis (EFA) to seven subcortical volumes in order to constrain the complexity of the input variables and ensure more stable clustering results. Factor scores derived from the EFA were used to build networks. A community detection (CD) algorithm clustered participants into subgroups based on the networks.ResultsExploratory factor analysis revealed three factors (basal ganglia, limbic system, and thalamus) in boys and men with and without ADHD. Factor structures for girls and women differed from those in males. Given sample size considerations, we concentrated subsequent analyses on males. Male participants could be separated into four communities, of which one was absent in healthy men. Significant case-control differences of subcortical volumes were observed within communities in boys, often with stronger effect sizes compared to the entire sample. As in the entire sample, none were observed in men. Affected men in two of the communities presented comorbidities more frequently than those in other communities. There were no significant differences in ADHD symptom severity, IQ, and medication use between communities in either boys or men.ConclusionsOur results indicate that neuroanatomic heterogeneity in subcortical volumes exists, irrespective of ADHD diagnosis. Effect sizes of case-control differences appear more pronounced at least in some of the subgroups.

To study the effect of host genetics on gut microbiome composition, the MiBioGen consortium curated and analyzed genome-wide genotypes and 16S fecal microbiome data from 18,340 individuals (24 cohorts). Microbial composition showed high variability across cohorts: only 9 of 410 genera were detected in more than 95% of samples. A genome-wide association study of host genetic variation regarding microbial taxa identified 31 loci affecting the microbiome at a genome-wide significant (P

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a highly heritable neurodevelopmental disorder, with onset in childhood and a considerable likelihood to persist into adulthood. Our previous work has identified that across adults and adolescents with ADHD, gray matter volume (GMV) alteration in the frontal cortex was consistently associated with working memory underperformance, and GMV alteration in the cerebellum was associated with inattention. Recent knowledge regarding ADHD genetic risk loci makes it feasible to investigate genomic factors underlying these persistent GMV alterations, potentially illuminating the pathology of ADHD persistence. Based on this, we applied a sparsity-constrained multivariate data fusion approach, sparse parallel independent component analysis, to GMV variations in the frontal and cerebellum regions and candidate risk single nucleotide polymorphisms (SNPs) data from 341 unrelated adult participants, including 167 individuals with ADHD, 47 unaffected siblings, and 127 healthy controls. We identified one SNP component significantly associated with one GMV component in superior/middle frontal regions and replicated this association in 317 adolescents from ADHD families. The association was stronger in individuals with ADHD than in controls, and stronger in adults and older adolescents than in younger ones. The SNP component highlights 93 SNPs in long non-coding RNAs mainly in chromosome 5 and 21 protein-coding genes that are significantly enriched in human neuron cells. Eighteen identified SNPs have regulation effects on gene expression, transcript expression, isoform percentage, or methylation level in frontal regions. Identified genes highlight MEF2C, CADM2, and CADPS2, which are relevant for modulating neuronal substrates underlying high-level cognition in ADHD, and their causality effects on ADHD persistence await further investigations. Overall, through a multivariate analysis, we have revealed a genomic pattern underpinning the frontal gray matter variation related to working memory deficit in ADHD.

Subcortical brain structures are integral to motion, consciousness, emotions and learning. We identified common genetic variation related to the volumes of the nucleus accumbens, amygdala, brainstem, caudate nucleus, globus pallidus, putamen and thalamus, using genome-wide association analyses in almost 40,000 individuals from CHARGE, ENIGMA and UK Biobank. We show that variability in subcortical volumes is heritable, and identify 48 significantly associated loci (40 novel at the time of analysis). Annotation of these loci by utilizing gene expression, methylation and neuropathological data identified 199 genes putatively implicated in neurodevelopment, synaptic signaling, axonal transport, apoptosis, inflammation/infection and susceptibility to neurological disorders. This set of genes is significantly enriched for Drosophila orthologs associated with neurodevelopmental phenotypes, suggesting evolutionarily conserved mechanisms. Our findings uncover novel biology and potential drug targets underlying brain development and disease.

Abstract Dietary habits may affect inflammatory status in humans. Here we explore this interaction as well as the potential mediating role of the gut microbiome (GM), given that the GM is both involved in processing of dietary components and influences the immune system. A cross-sectional analysis of a sample of 482 healthy participants (207 males and 275 females) was performed. Dietary intake was assessed by a semiquantitative food questionnaire. Adipokines and soluble inflammatory mediators were assayed with multiple immunoassays and ELISA. Microbial DNA was extracted from frozen stool samples of 471 participants. Polychoric correlation analysis was used to establish dietary patterns, and joint multivariate associations between these dietary patterns and immune biomarkers were studied using regression analyses with adjustment for sex, age, BMI, smoking, education levels and physical exercise and other dietary patterns. Non-parametric entropy mediation was applied to investigate whether diet-immune relationships are mediated by abundance of microbial species. In this cohort, we identified three dietary patterns, characterized as “high-meat” (meat and sweetened drink), “prudent diet” (fish, fruit, legumes and vegetables) and “high alcohol” (higher alcohol consumption). Higher adherence to prudent diet was associated with a higher adiponectin level. The high alcohol pattern was associated with high concentrations of circulating concentrations of pro-inflammatory markers (CRP, IL-6, VEGF). Dialister invisus was found to mediate the relationship between a prudent dietary pattern and adiponectin, AAT, CRP, IL-6, and VEGF. In conclusion, a meat-based diet and a diet with high alcohol consumption were associated with high concentrations of biomarkers of chronic low-grade inflammation, and conversely, a prudent diet was associated with anti-inflammatory biomarkers. Diet-inflammation regulation may differ between sexes. Mediation analyses revealed that the association between prudent diet and immune function was partially mediated by the GM. The study adds to our understanding of the associations between diet, the immune system and the GM in a healthy population.

Abstract Compelling evidence supports alterations in gut microbial diversity, bacterial composition, and/or relative abundance of several bacterial taxa in attention-deficit/hyperactivity disorder (ADHD). However, findings for ADHD are inconsistent among studies, and specific gut microbiome signatures for the disorder remain unknown. Given that previous studies have mainly focused on the pediatric form of the disorder and involved small sample sizes, we conducted the largest study to date to compare the gastrointestinal microbiome composition in 100 medication-naïve adults with ADHD and 100 sex-matched healthy controls. We found evidence that ADHD subjects have differences in the relative abundance of several microbial taxa. At the family level, our data support a lower relative abundance of Gracilibacteraceae and higher levels of Selenomonadaceae and Veillonellaceae in adults with ADHD. In addition, the ADHD group showed higher levels of Dialister and Megamonas and lower abundance of Anaerotaenia and Gracilibacter at the genus level. All four selected genera explained 15% of the variance of ADHD, and this microbial signature achieved an overall sensitivity of 74% and a specificity of 71% for distinguishing between ADHD patients and healthy controls. We also tested whether the selected genera correlate with age, body mass index (BMI), or scores of the ADHD rating scale but found no evidence of correlation between genera relative abundance and any of the selected traits. These results are in line with recent studies supporting gut microbiome alterations in neurodevelopment disorders, but further studies are needed to elucidate the role of the gut microbiota on the ADHD across the lifespan and its contribution to the persistence of the disorder from childhood to adulthood.

BackgroundAttention-deficit/hyperactivity disorder (ADHD) and bipolar disorder (BPD) are frequently co-occurring and highly heritable mental health conditions. We hypothesized that BPD cases with an early age of onset (≤21 years old) would be particularly likely to show genetic covariation with ADHD.MethodsGenome-wide association study data were available for 4609 individuals with ADHD, 9650 individuals with BPD (5167 thereof with early-onset BPD), and 21,363 typically developing controls. We conducted a cross-disorder genome-wide association study meta-analysis to identify whether the observed comorbidity between ADHD and BPD could be due to shared genetic risks.ResultsWe found a significant single nucleotide polymorphism-based genetic correlation between ADHD and BPD in the full and age-restricted samples (rGfull = .64, p = 3.13 × 10-14; rGrestricted = .71, p = 4.09 × 10-16). The meta-analysis between the full BPD sample identified two genome-wide significant (prs7089973 = 2.47 × 10-8; prs11756438 = 4.36 × 10-8) regions located on chromosomes 6 (CEP85L) and 10 (TAF9BP2). Restricting the analyses to BPD cases with an early onset yielded one genome-wide significant association (prs58502974 = 2.11 × 10-8) on chromosome 5 in the ADCY2 gene. Additional nominally significant regions identified contained known expression quantitative trait loci with putative functional consequences for NT5DC1, NT5DC2, and CACNB3 expression, whereas functional predictions implicated ABLIM1 as an allele-specific expressed gene in neuronal tissue.ConclusionsThe single nucleotide polymorphism-based genetic correlation between ADHD and BPD is substantial, significant, and consistent with the existence of genetic overlap between ADHD and BPD, with potential differential genetic mechanisms involved in early and later BPD onset.

The hippocampal formation is a brain structure integrally involved in episodic memory, spatial navigation, cognition and stress responsiveness. Structural abnormalities in hippocampal volume and shape are found in several common neuropsychiatric disorders. To identify the genetic underpinnings of hippocampal structure here we perform a genome-wide association study (GWAS) of 33,536 individuals and discover six independent loci significantly associated with hippocampal volume, four of them novel. Of the novel loci, three lie within genes (ASTN2, DPP4 and MAST4) and one is found 200 kb upstream of SHH. A hippocampal subfield analysis shows that a locus within the MSRB3 gene shows evidence of a localized effect along the dentate gyrus, subiculum, CA1 and fissure. Further, we show that genetic variants associated with decreased hippocampal volume are also associated with increased risk for Alzheimer's disease (rg=-0.155). Our findings suggest novel biological pathways through which human genetic variation influences hippocampal volume and risk for neuropsychiatric illness.

In this review, we discuss recent work by the ENIGMA Consortium (http://enigma.ini.usc.edu) - a global alliance of over 500 scientists spread across 200 institutions in 35 countries collectively analyzing brain imaging, clinical, and genetic data. Initially formed to detect genetic influences on brain measures, ENIGMA has grown to over 30 working groups studying 12 major brain diseases by pooling and comparing brain data. In some of the largest neuroimaging studies to date - of schizophrenia and major depression - ENIGMA has found replicable disease effects on the brain that are consistent worldwide, as well as factors that modulate disease effects. In partnership with other consortia including ADNI, CHARGE, IMAGEN and others1, ENIGMA's genomic screens - now numbering over 30,000 MRI scans - have revealed at least 8 genetic loci that affect brain volumes. Downstream of gene findings, ENIGMA has revealed how these individual variants - and genetic variants in general - may affect both the brain and risk for a range of diseases. The ENIGMA consortium is discovering factors that consistently affect brain structure and function that will serve as future predictors linking individual brain scans and genomic data. It is generating vast pools of normative data on brain measures - from tens of thousands of people - that may help detect deviations from normal development or aging in specific groups of subjects. We discuss challenges and opportunities in applying these predictors to individual subjects and new cohorts, as well as lessons we have learned in ENIGMA's efforts so far.

Intracranial volume reflects the maximally attained brain size during development, and remains stable with loss of tissue in late life. It is highly heritable, but the underlying genes remain largely undetermined. In a genome-wide association study of 32,438 adults, we discovered five previously unknown loci for intracranial volume and confirmed two known signals. Four of the loci were also associated with adult human stature, but these remained associated with intracranial volume after adjusting for height. We found a high genetic correlation with child head circumference (ρgenetic = 0.748), which indicates a similar genetic background and allowed us to identify four additional loci through meta-analysis (Ncombined = 37,345). Variants for intracranial volume were also related to childhood and adult cognitive function, and Parkinson's disease, and were enriched near genes involved in growth pathways, including PI3K-AKT signaling. These findings identify the biological underpinnings of intracranial volume and their link to physiological and pathological traits.

Abstract Stress negatively affects cognitive performance. Probiotics remediate somatic and behavioral stress responses, hypothetically by acting on the gut microbiota. Here, in exploratory analyses, we assessed gut microbial alterations after 28-days supplementation of multi-strain probiotics (EcologicBarrier consisting of Lactobacilli, Lactococci, and Bifidobacteria in healthy, female subjects (probiotics group n = 27, placebo group n = 29). In an identical pre-session and post-session, subjects performed a working memory task before and after an acute stress intervention. Global gut microbial beta diversity changed over time, but we were not able to detect differences between intervention groups. At the taxonomic level, Time by Intervention interactions were not significant after multiple comparison correction; the relative abundance of eight genera in the probiotics group was higher (uncorrected) relative to the placebo group: Butyricimonas, Parabacteroides, Alistipes, Christensenellaceae_R-7_group, Family_XIII_AD3011_group, Ruminococcaceae_UCG-003, Ruminococcaceae_UCG-005, and Ruminococcaceae_UCG-010. In a second analysis step, association analyses were done only within this selection of microbial genera, revealing the probiotics-induced change in genus Ruminococcaceae_UCG-003 was significantly associated with probiotics’ effect on stress-induced working memory changes (r spearman(27) = 0.565; pFDR = 0.014) in the probiotics group only and independent of potential confounders (i.e., age, BMI, and baseline dietary fiber intake). That is subjects with a higher increase in Ruminococcaceae_UCG-003 abundance after probiotics were also more protected from negative effects of stress on working memory after probiotic supplementation. The bacterial taxa showing an increase in relative abundance in the probiotics group are plant fiber degrading bacteria and produce short-chain fatty acids that are known for their beneficial effect on gut and brain health, e.g., maintaining intestinal-barrier and blood–brain-barrier integrity. This study shows that gut microbial alterations, modulated through probiotics use, are related to improved cognitive performance in acute stress circumstances.

Abstract Attention-deficit/hyperactivity disorder (ADHD) is a childhood-onset neuropsychiatric disorder and may persist into adulthood. Working memory and attention deficits have been reported to persist from childhood to adulthood. How neuronal underpinnings of deficits differ across adolescence and adulthood is not clear. In this study, we investigated gray matter of two cohorts, 486 adults and 508 adolescents, each including participants from ADHD and healthy controls families. Two cohorts both presented significant attention and working memory deficits in individuals with ADHD. Independent component analysis was applied to the gray matter of each cohort, separately, to extract cohort-inherent networks. Then, we identified gray matter networks associated with inattention or working memory in each cohort, and projected them onto the other cohort for comparison. Two components in the inferior, middle/superior frontal regions identified in adults and one component in the insula and inferior frontal region identified in adolescents were significantly associated with working memory in both cohorts. One component in bilateral cerebellar tonsil and culmen identified in adults and one component in left cerebellar region identified in adolescents were significantly associated with inattention in both cohorts. All these components presented a significant or nominal level of gray matter reduction for ADHD participants in adolescents, but only one showed nominal reduction in adults. Our findings suggest although the gray matter reduction of these regions may not be indicative of persistency of ADHD, their persistent associations with inattention or working memory indicate an important role of these regions in the mechanism of persistence or remission of the disorder.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition, of-ten persistent into adulthood and accompanied by reactive aggression. Associations of diet and the gut-microbiome with ADHD as well as emotional behaviors suggest potential clinical rele-vance of both. However, studies on diet and the gut-microbiome in human reactive aggression are lacking, and should investigate the interaction between diet and the gut-microbiome leading to behavioral changes to assess their potential clinical relevance. In this study, we investigated the interaction of diet and gut-microbiota with adult ADHD and reactive aggression in 77 adults with ADHD and 76 neurotypical individuals. We studied the relationships of ADHD and reactive ag-gression with dietary patterns, bacterial community and taxonomic differences of 16S-sequenced fecal microbiome samples, and potential mediating effects of bacterial genus abundance on signifi-cant diet-behavior associations. The key findings include: (1) An association of high-energy intake with reactive aggeression scores (pFDR = 4.01 × 10−02); (2) Significant associations of several genera with either reactive aggression or ADHD diagnosis with no overlap; and (3) No significant mediation effects of the selected genera on the association of reactive aggression with the high-energy diet. Our results suggest that diet and the microbiome are linked to reactive aggression and/or ADHD individually, and highlight the need to further study the way diet and the gut-microbiome inter-act. [ABSTRACT FROM AUTHOR]

Despite not being part of the core diagnostic criteria for attention-deficit/hyperactivity disorder (ADHD), emotion dysregulation is a highly prevalent and clinically important component of (adult) ADHD. Emotionally dysregulated behaviors such as reactive aggression have a significant impact on the functional outcome in ADHD. However, little is known about the mechanisms underlying reactive aggression in ADHD. In this study, we aimed to identify the neural correlates of reactive aggression as a measure of emotionally dysregulated behavior in adults with persistent ADHD during implicit emotion regulation processes. We analyzed associations of magnetic resonance imaging-based whole-brain activity during a dynamic facial expression task with levels of reactive aggression in 78 adults with and 78 adults without ADHD, and also investigated relationships of reactive aggression with symptoms and impairments. While participants with ADHD had higher reactive aggression scores than controls, the neural activation patterns of both groups to processing of emotional faces were similar. However, investigating the brain activities associated with reactive aggression in individuals with and without ADHD showed an interaction of diagnosis and reactive aggression scores. We found high levels of activity in the right insula, the hippocampus, and middle and superior frontal areas to be particularly associated with high reactive aggression scores within the ADHD group. Furthermore, the limbic activity was associated with more hyperactivity/impulsivity symptoms. These results suggest a partly differential mechanism associated with reactive aggression in ADHD as compared to controls. Emotional hyper-reactivity in the salience network as well as more effortful top–down regulation from the self-regulation network might contribute to emotionally dysregulated behavior as measured by reactive aggression.

BackgroundIt is widely acknowledged that comorbidity between psychiatric disorders is common. Shared and diverse underpinnings of psychiatric disorders cannot be systematically understood based on symptom-based categories of mental disorders, which map poorly onto pathophysiological mechanisms. In the Measuring Integrated Novel Dimensions in Neurodevelopmental and Stress-Related Mental Disorders (MIND-SET) study, we make use of current concepts of comorbidity that transcend the current diagnostic categories. We test this approach to psychiatric problems in patients with frequently occurring psychiatric disorders and their comorbidities (excluding psychosis). ObjectiveThe main aim of the MIND-SET project is to determine the shared and specific mechanisms of neurodevelopmental and stress-related psychiatric disorders at different observational levels. MethodsThis is an observational cross-sectional study. Data from different observational levels as defined in the Research Domain Criteria (genetics, physiology, neuropsychology, system-level neuroimaging, behavior, self-report, and experimental neurocognitive paradigms) are collected over four time points. Included are adult (aged ≥18 years), nonpsychotic, psychiatric patients with a clinical diagnosis of a stress-related disorder (mood disorder, anxiety disorder, or substance use disorder) or a neurodevelopmental disorder (autism spectrum disorder or attention-deficit/hyperactivity disorder). Individuals with no current or past psychiatric diagnosis are included as neurotypical controls. Data collection started in June 2016 with the aim to include a total of 650 patients and 150 neurotypical controls by 2021. The data collection procedure includes online questionnaires and three subsequent sessions with (1) standardized clinical examination, physical examination, and blood sampling; (2) psychological constructs, neuropsychological tests, and biological marker sampling; and (3) neuroimaging measures. ResultsWe aim to include a total of 650 patients and 150 neurotypical control participants in the time period between 2016 and 2022. In October 2021, we are at 95% of our target. ConclusionsThe MIND-SET study enables us to investigate the mechanistic underpinnings of nonpsychotic psychiatric disorders transdiagnostically. We will identify both shared and disorder-specific markers at different observational levels that can be used as targets for future diagnostic and treatment approaches.

Extraversion is a relatively stable and heritable personality trait associated with numerous psychosocial, lifestyle and health outcomes. Despite its substantial heritability, no genetic variants have been detected in previous genome-wide association (GWA) studies, which may be due to relatively small sample sizes of those studies. Here, we report on a large meta-analysis of GWA studies for extraversion in 63,030 subjects in 29 cohorts. Extraversion item data from multiple personality inventories were harmonized across inventories and cohorts. No genome-wide significant associations were found at the single nucleotide polymorphism (SNP) level but there was one significant hit at the gene level for a long non-coding RNA site (LOC101928162). Genome-wide complex trait analysis in two large cohorts showed that the additive variance explained by common SNPs was not significantly different from zero, but polygenic risk scores, weighted using linkage information, significantly predicted extraversion scores in an independent cohort. These results show that extraversion is a highly polygenic personality trait, with an architecture possibly different from other complex human traits, including other personality traits. Future studies are required to further determine which genetic variants, by what modes of gene action, constitute the heritable nature of extraversion.

Schizophrenia is a devastating psychiatric illness with high heritability. Brain structure and function differ, on average, between people with schizophrenia and healthy individuals. As common genetic associations are emerging for both schizophrenia and brain imaging phenotypes, we can now use genome-wide data to investigate genetic overlap. Here we integrated results from common variant studies of schizophrenia (33,636 cases, 43,008 controls) and volumes of several (mainly subcortical) brain structures (11,840 subjects). We did not find evidence of genetic overlap between schizophrenia risk and subcortical volume measures either at the level of common variant genetic architecture or for single genetic markers. These results provide a proof of concept (albeit based on a limited set of structural brain measures) and define a roadmap for future studies investigating the genetic covariance between structural or functional brain phenotypes and risk for psychiatric disorders.

Abstract Background Food may trigger Attention-Deficit/Hyperactivity Disorder (ADHD) symptoms. Therefore, an elimination diet (ED) might be an effective treatment for children with ADHD. However, earlier studies were criticized for the nature of the control group, potential confounders explaining the observed effects, unsatisfactory blinding, potential risks of nutritional deficiencies and unknown long term and cost-effectiveness. To address these issues, this paper describes the rationale, study design and methods of an ongoing two arm randomized controlled trial (RCT) comparing the short (5 week) and long term (1 year) effects of an elimination diet and a healthy diet compared with care as usual (CAU) in children with ADHD. Methods A total of N = 162 children (5–12 years) with ADHD will be randomized to either an ED or a healthy diet. A comparator arm including N = 60 children being solely treated with CAU (e.g. medication) is used to compare the effects found in both dietary groups. The two armed RCT is performed in two youth psychiatry centers in the Netherlands, with randomization within each participating center. The primary outcome measure is response to treatment defined as a ≥ 30% reduction on an ADHD DSM-5 rating scale (SWAN) and/or on an emotion dysregulation rating scale (SDQ: dysregulation profile). This is assessed after 5 weeks of dietary treatment, after which participants continue the diet or not. Secondary outcome measures include the Disruptive Behavior Diagnostic Observational Schedule (DB-DOS), parent and teacher ratings of comorbid symptoms, cognitive assessment (e.g. executive functions), school functioning, physical measurements (e.g. weight), motor activity, sleep pattern, food consumption, nutritional quality of the diet, adherence, parental wellbeing, use of health care resources and cost-effectiveness. Assessments take place at the start of the study (T0), after five weeks (T1), four months (T2), eight months (T3) and 12 months of treatment (T4). T0, T1 and T4 assessments take place at one of the psychiatric centers. T2 and T3 assessments consist of filling out online questionnaires by the parents only. Discussion This RCT will likely contribute significantly to clinical practice for ADHD by offering insight into the feasibility, nutritional quality, (cost-)effectiveness and long term effects of dietary treatments for ADHD. Trial registration www.trialregister.nl , NTR5434 . Registered at October 11th, 2015.

Abstract Background The impact of the gut microbiota on host physiology and behavior has been relatively well established. Whether changes in microbial composition affect brain structure and function is largely elusive, however. This is important as altered brain structure and function have been implicated in various neurodevelopmental disorders, like attention-deficit/hyperactivity disorder (ADHD). We hypothesized that gut microbiota of persons with and without ADHD, when transplanted into mice, would differentially modify brain function and/or structure. We investigated this by colonizing young, male, germ-free C57BL/6JOlaHsd mice with microbiota from individuals with and without ADHD. We generated and analyzed microbiome data, assessed brain structure and function by magnetic resonance imaging (MRI), and studied mouse behavior in a behavioral test battery. Results Principal coordinate analysis showed a clear separation of fecal microbiota of mice colonized with ADHD and control microbiota. With diffusion tensor imaging, we observed a decreased structural integrity of both white and gray matter regions (i.e., internal capsule, hippocampus) in mice that were colonized with ADHD microbiota. We also found significant correlations between white matter integrity and the differentially expressed microbiota. Mice colonized with ADHD microbiota additionally showed decreased resting-state functional MRI-based connectivity between right motor and right visual cortices. These regions, as well as the hippocampus and internal capsule, have previously been reported to be altered in several neurodevelopmental disorders. Furthermore, we also show that mice colonized with ADHD microbiota were more anxious in the open-field test. Conclusions Taken together, we demonstrate that altered microbial composition could be a driver of altered brain structure and function and concomitant changes in the animals’ behavior. These findings may help to understand the mechanisms through which the gut microbiota contributes to the pathobiology of neurodevelopmental disorders. Video abstract.

ImportanceNeuroticism is a pervasive risk factor for psychiatric conditions. It genetically overlaps with major depressive disorder (MDD) and is therefore an important phenotype for psychiatric genetics. The Genetics of Personality Consortium has created a resource for genome-wide association analyses of personality traits in more than 63,000 participants (including MDD cases).ObjectivesTo identify genetic variants associated with neuroticism by performing a meta-analysis of genome-wide association results based on 1000 Genomes imputation; to evaluate whether common genetic variants as assessed by single-nucleotide polymorphisms (SNPs) explain variation in neuroticism by estimating SNP-based heritability; and to examine whether SNPs that predict neuroticism also predict MDD.Design, setting, and participantsGenome-wide association meta-analysis of 30 cohorts with genome-wide genotype, personality, and MDD data from the Genetics of Personality Consortium. The study included 63,661 participants from 29 discovery cohorts and 9786 participants from a replication cohort. Participants came from Europe, the United States, or Australia. Analyses were conducted between 2012 and 2014.Main outcomes and measuresNeuroticism scores harmonized across all 29 discovery cohorts by item response theory analysis, and clinical MDD case-control status in 2 of the cohorts.ResultsA genome-wide significant SNP was found on 3p14 in MAGI1 (rs35855737; P = 9.26 × 10-9 in the discovery meta-analysis). This association was not replicated (P = .32), but the SNP was still genome-wide significant in the meta-analysis of all 30 cohorts (P = 2.38 × 10-8). Common genetic variants explain 15% of the variance in neuroticism. Polygenic scores based on the meta-analysis of neuroticism in 27 cohorts significantly predicted neuroticism (1.09 × 10-12

The highly complex structure of the human brain is strongly shaped by genetic influences. Subcortical brain regions form circuits with cortical areas to coordinate movement, learning, memory and motivation, and altered circuits can lead to abnormal behaviour and disease. To investigate how common genetic variants affect the structure of these brain regions, here we conduct genome-wide association studies of the volumes of seven subcortical regions and the intracranial volume derived from magnetic resonance images of 30,717 individuals from 50 cohorts. We identify five novel genetic variants influencing the volumes of the putamen and caudate nucleus. We also find stronger evidence for three loci with previously established influences on hippocampal volume and intracranial volume. These variants show specific volumetric effects on brain structures rather than global effects across structures. The strongest effects were found for the putamen, where a novel intergenic locus with replicable influence on volume (rs945270; P = 1.08 × 10(-33); 0.52% variance explained) showed evidence of altering the expression of the KTN1 gene in both brain and blood tissue. Variants influencing putamen volume clustered near developmental genes that regulate apoptosis, axon guidance and vesicle transport. Identification of these genetic variants provides insight into the causes of variability in human brain development, and may help to determine mechanisms of neuropsychiatric dysfunction.

Research on the gut–brain axis has accelerated substantially over the course of the last years. Many reviews have outlined the important implications of understanding the relation of the gut microbiota with human brain function and behavior. One substantial drawback in integrating gut microbiome and brain data is the lack of integrative multivariate approaches that enable capturing variance in both modalities simultaneously. To address this issue, we applied a linked independent component analysis (LICA) to microbiota and brain connectivity data.We analyzed data from 58 healthy females (mean age = 21.5 years). Magnetic Resonance Imaging data were acquired using resting state functional imaging data. The assessment of gut microbial composition from feces was based on sequencing of the V4 16S rRNA gene region. We used the LICA model to simultaneously factorize the subjects’ large-scale brain networks and microbiome relative abundance data into 10 independent components of spatial and abundance variation.LICA decomposition resulted in four components with non-marginal contribution of the microbiota data. The default mode network featured strongly in three components, whereas the two-lateralized fronto-parietal attention networks contributed to one component. The executive-control (with the default mode) network was associated to another component. We found that the abundance of Prevotella genus was associated with the strength of expression of all networks, whereas Bifidobacterium was associated with the default mode and frontoparietal-attention networks.We provide the first exploratory evidence for multivariate associative patterns between the gut microbiota and brain network connectivity in healthy humans considering the complexity of both systems.

Gray matter disruptions have been found consistently in Attention-deficit/Hyperactivity Disorder (ADHD). The organization of these alterations into brain structural networks remains largely unexplored. We investigated 508 participants (281 males) with ADHD (N = 210), their unaffected siblings (N = 108), individuals with subthreshold ADHD (N = 49), and unrelated healthy controls (N = 141) with an age range from 7 to 18 years old from 336 families in the Dutch NeuroIMAGE project. Source based morphometry was used to examine structural brain network alterations and their association with symptoms and cognitive performance. Two networks showed significant reductions in individuals with ADHD compared to unrelated healthy controls after False Discovery Rate correction. Component A, mainly located in bilateral Crus I, showed a ADHD/typically developing difference with subthreshold cases being intermediate between ADHD and typically developing controls. The unaffected siblings were similar to controls. After correcting for IQ and medication status, component A showed a negative correlation with inattention symptoms across the entire sample. Component B included a maximum cluster in the bilateral insula, where unaffected siblings, similar to individuals with ADHD, showed significantly reduced loadings compared to controls; but no relationship with individual symptoms or cognitive measures was found for component B. This multivariate approach suggests that areas reflecting genetic liability within ADHD are partly separate from those areas modulating symptom severity.

Abstract Background The effects of gut microbiota on human traits are expected to be small to moderate and adding the complexity of the human diseases, microbiome research demands big sample sizes. Fecal samples for such studies are mostly self-collected by participants at home. This imposes an extra level of complexity as sample collection and storage can be challenging. Effective, low-burden collection and storage methods allowing fecal samples to be transported properly and ensuring optimal quality and quantity of bacterial DNA for upstream analyses are necessary. Moreover, accurate assessment of the microbiome composition also depends on bacterial DNA extraction method. The aim of this study was to evaluate the reliability and efficiency of the OMNIgene•GUT kit as a participant-fecal friendly collection method (storage at room temperature for 24 h (O24h) or 7 days (O7d)) in comparison to the standard collection method (Fresh, storage at 4 °C for less than 24 h) in terms of amount of variability and information content accounting for two common DNA extraction methods. Results Fourteen fecal samples were collected from healthy individuals (7 males, 7 females). Collection and storage methods did not differ significantly in terms of DNA concentration and Shannon diversity index. Phylum relative abundance showed significant differences for Bacteroidetes, Actinobacteria and Cyanobacteria. The differences were observed between control (Fresh) and O24h methods, but not between Fresh and O7d. These differences were not seen when performing bacterial DNA quantification based on three bacterial groups: Bacteroides spp., Bifidobacterium spp. and Clostridium cluster IV, which represent three major phyla: Bacteroidetes, Actinobacteria and Firmicutes respectively. The two DNA extraction methods differ in terms of DNA quantity, quality, bacterial diversity and bacterial relative abundance. Furthermore, principal component analysis revealed differences in microbial structure, which are driven by the DNA extraction methods more than the collection/storage methods. Conclusion Our results have highlighted the potential of using the OMNIgene•GUT kit for collection and storage at ambient temperature, which is convenient for studies aiming to collect large samples by giving participants the possibility to send samples by post. Importantly, we revealed that the choice of DNA extraction method have an impact on the microbiome profiling.

While gray matter (GM) anomalies have been reported for attention-deficit/hyperactivity disorder (ADHD), investigating their associations with cognitive deficits and individual symptom domains can help pinpoint the neural underpinnings critical for the pathology of ADHD, particularly the persist form of ADHD. In this work, we performed both independent component analysis and voxel-based morphometry analysis on whole brain GM of 486 adults including 214 patients, 96 unaffected siblings, and 176 healthy controls, in relation to cognition and symptoms. Independent component analysis revealed that higher GM volume in inferior semilunar lobule, inferior frontal gyri, and superior and middle frontal gyri was associated with better working memory performance, and lower GM volume in cerebellar tonsil and culmen was associated with more severe inattention symptoms. Consistently, voxel-based morphometry analysis showed that higher GM volume in multiple regions of frontal lobe, cerebellum and temporal lobe was related to better working memory performance. Focusing on the networks derived from ICA, our results integrated prefrontal regions and cerebellar regions through associations with working memory and inattention symptoms, lending support for the theory of ‘cool’-cognition dysfunction being mediated by inferior fronto-striato-cerebellar networks in ADHD. Siblings showed intermediate cognitive impairments between patients and controls but presented GM anomalies in unique focal regions, suggesting they are a separate group potentially affected by the shared genetic and environmental risks with ADHD patients. Keywords: Adult ADHD, Independent component analysis, Prefrontal cortex, Cerebellum, Working memory