Publications by authors named "Alejandro Arias-Vasquez"

133 Publications

Do Breastfeeding History and Diet Quality Predict Inhibitory Control at Preschool Age?

Nutrients 2021 Aug 10;13(8). Epub 2021 Aug 10.

Department of Cognitive Neuroscience, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, 6525 EN Nijmegen, The Netherlands.

Inhibitory control is the ability to control impulsive behavior. It is associated with a range of mental and physical health outcomes, including attention deficit hyperactivity disorder and substance dependence. Breastfeeding and healthy dietary patterns have been associated with better executive functions, of which inhibitory control is part. Additionally, breastfeeding has been associated with healthy dietary patterns. Following our preregistration in the Open Science Framework, we investigated the associations between breastfeeding history and inhibitory control at preschool age, with habitual diet quality as a potential mediating factor. A total of 72 families from a longitudinal study participated at child age 3. Breastfeeding questionnaires were administered at 2, 6, and 12 weeks, and at 12 and 36 months. Six inhibitory control tasks were performed during a home visit, and questionnaires were filled in by both parents. Diet quality at age 3 was assessed via three unannounced 24-h recalls. Structural equation modelling was performed in R. This study did not provide evidence that breastfeeding history is associated with inhibitory control in 3-year-old children. Furthermore, diet quality at age 3 did not mediate the link between breastfeeding history and inhibitory control. Previous studies have investigated broader aspects of inhibitory control, such as executive functions, and used different methods to assess nutritional intake, which might explain our differential findings. Our findings contribute to the growing literature on associations between nutrition and behavior. Future replications with larger and more diverse preschool samples are recommended.
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http://dx.doi.org/10.3390/nu13082752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8398217PMC
August 2021

Effects of the Mediterranean Diet or Nut Consumption on Gut Microbiota Composition and Fecal Metabolites and their Relationship with Cardiometabolic Risk Factors.

Mol Nutr Food Res 2021 Jul 31:e2000982. Epub 2021 Jul 31.

Department of Biochemistry and Biotechnology, Faculty of Medicine and Health Sciences, University RoviraiVirgili (URV), Reus, Spain.

Scope: To examine whether a Mediterranean Diet (MedDiet) compared to the consumption of nuts in the context of a habitual non-MedDiet exerts a greater beneficial effect on gut microbiota and fecal metabolites; thus, contributing to explain major benefits on cardiometabolic risk factors.

Methods And Results: Fifty adults with Metabolic Syndrome are randomized to a controlled, crossover 2-months dietary-intervention trial with a 1-month wash-out period, following a MedDiet or consuming nuts (50 g day ). Microbiota composition is assessed by 16S rRNA gene sequencing and metabolites are measured using Nuclear Magnetic Resonance (NMR) and liquid chromatography coupled to triple quadrupole mass spectrometry (LC-qTOF) platforms in a targeted metabolomics approach. Decreased glucose, insulin and the homeostatic model assessment of insulin resistance (HOMA-IR) is observed after the MedDiet compared to the nuts intervention. Relative abundances of Lachnospiraceae NK4A136 and an uncultured genera of Ruminococcaceae are significantly increased after the MedDiet compared to nuts supplementation. Changes in Lachnospiraceae NK4A136 are inversely associated with insulin levels and HOMA-IR, while positively and negatively with changes in cholate and cadaverine, respectively.

Conclusions: Following a MedDiet, rather than nuts, induces a significant increase in Lachnospiraceae NK4A136 and improves the metabolic risk. This genera seems to affect the bile acid metabolism and cadaverine which may account for the improvement in insulin levels.
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http://dx.doi.org/10.1002/mnfr.202000982DOI Listing
July 2021

Gut microbiota signature in treatment-naïve attention-deficit/hyperactivity disorder.

Transl Psychiatry 2021 07 8;11(1):382. Epub 2021 Jul 8.

Department of Psychiatry, Mental Health and Addictions, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain.

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.
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http://dx.doi.org/10.1038/s41398-021-01504-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8266901PMC
July 2021

Correction: Szopinska-Tokov et al. Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms. 2020, , 406.

Microorganisms 2021 Jun 23;9(7). Epub 2021 Jun 23.

Department of Psychiatry, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6525 GA Nijmegen, The Netherlands.

The authors wish to make the following correction to this paper [...].
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http://dx.doi.org/10.3390/microorganisms9071358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8306196PMC
June 2021

Diet, Physical Activity, and Disinhibition in Middle-Aged and Older Adults: A UK Biobank Study.

Nutrients 2021 May 11;13(5). Epub 2021 May 11.

Interdisciplinary Center Psychopathology and Emotion Regulation, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

Disinhibition is a prominent feature of multiple psychiatric disorders, and has been associated with poor long-term somatic outcomes. Modifiable lifestyle factors including diet and moderate-to-vigorous physical activity (MVPA) may be associated with disinhibition, but their contributions have not previously been quantified among middle-aged/older adults. Here, among N = 157,354 UK Biobank participants aged 40-69, we extracted a single disinhibition principal component and four dietary components (prudent diet, elimination of wheat/dairy/eggs, meat consumption, full-cream dairy consumption). In addition, latent profile analysis assigned participants to one of five empirical dietary groups: prudent-moderate, unhealthy, restricted, meat-avoiding, low-fat dairy. Disinhibition was regressed on the four dietary components, the dietary grouping variable, and self-reported MVPA. In men and women, disinhibition was negatively associated with prudent diet, and positively associated with wheat/dairy/eggs elimination. In men, disinhibition was also associated with consumption of meat and full-cream dairy products. Comparing groups, disinhibition was lower in the prudent-moderate diet (reference) group compared to all other groups. Absolute βs ranged from 0.02-0.13, indicating very weak effects. Disinhibition was not associated with MVPA. In conclusion, disinhibition is associated with multiple features of diet among middle-aged/older adults. Our findings foster specific hypotheses (e.g., early malnutrition, elevated immune-response) to be tested in alternative study designs.
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http://dx.doi.org/10.3390/nu13051607DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8151887PMC
May 2021

Probiotics-induced changes in gut microbial composition and its effects on cognitive performance after stress: exploratory analyses.

Transl Psychiatry 2021 05 20;11(1):300. Epub 2021 May 20.

Donders Institute for Brain Cognition and Behaviour, Centre for Cognitive Neuroimaging, Radboud University, Nijmegen, the Netherlands.

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(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.
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http://dx.doi.org/10.1038/s41398-021-01404-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8137885PMC
May 2021

Characterizing neuroanatomic heterogeneity in people with and without ADHD based on subcortical brain volumes.

J Child Psychol Psychiatry 2021 Sep 30;62(9):1140-1149. Epub 2021 Mar 30.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: Attention-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.

Methods: Using 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.

Results: Exploratory 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.

Conclusions: Our 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.
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http://dx.doi.org/10.1111/jcpp.13384DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403135PMC
September 2021

Discrepancies of polygenic effects on symptom dimensions between adolescents and adults with ADHD.

Psychiatry Res Neuroimaging 2021 05 20;311:111282. Epub 2021 Mar 20.

Department of Psychology, Georgia State University, United States; Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University, Georgia Institute of Technology and Emory University, USA; Neuroscience Institute, Georgia State University, USA.

A significant proportion of individuals with attention-deficit/hyperactivity disorder (ADHD) show persistence into adulthood. The genetic and neural correlates of ADHD in adolescents versus adults remain poorly characterized. We investigated ADHD polygenic risk score (PRS) in relation to previously identified gray matter (GM) patterns, neurocognitive, and symptom findings in the same ADHD sample (462 adolescents & 422 adults from the NeuroIMAGE and IMpACT cohorts). Significant effects of ADHD PRS were found on hyperactivity and impulsivity symptoms in adolescents, hyperactivity symptom in adults, but not GM volume components. A distinct PRS effect between adolescents and adults on individual ADHD symptoms is suggested.
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http://dx.doi.org/10.1016/j.pscychresns.2021.111282DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8058322PMC
May 2021

Gray matter networks associated with attention and working memory deficit in ADHD across adolescence and adulthood.

Transl Psychiatry 2021 03 25;11(1):184. Epub 2021 Mar 25.

Tri-institutional Center for Translational Research in Neuroimaging and Data Science (TReNDS), Georgia State University Georgia Institute of Technology and Emory University, Atlanta, GA, USA.

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.
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http://dx.doi.org/10.1038/s41398-021-01301-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7994833PMC
March 2021

Sialylated human milk oligosaccharides program cognitive development through a non-genomic transmission mode.

Mol Psychiatry 2021 Mar 4. Epub 2021 Mar 4.

Centre for Behavioural Sciences and Mental Health, Istituto Superiore di Sanità, Rome, Italy.

Breastmilk contains bioactive molecules essential for brain and cognitive development. While sialylated human milk oligosaccharides (HMOs) have been implicated in phenotypic programming, their selective role and underlying mechanisms remained elusive. Here, we investigated the long-term consequences of a selective lactational deprivation of a specific sialylated HMO in mice. We capitalized on a knock-out (KO) mouse model (B6.129-St6gal1/J) lacking the gene responsible for the synthesis of sialyl(alpha2,6)lactose (6'SL), one of the two sources of sialic acid (Neu5Ac) to the lactating offspring. Neu5Ac is involved in the formation of brain structures sustaining cognition. To deprive lactating offspring of 6'SL, we cross-fostered newborn wild-type (WT) pups to KO dams, which provide 6'SL-deficient milk. To test whether lactational 6'SL deprivation affects cognitive capabilities in adulthood, we assessed attention, perseveration, and memory. To detail the associated endophenotypes, we investigated hippocampal electrophysiology, plasma metabolomics, and gut microbiota composition. To investigate the underlying molecular mechanisms, we assessed gene expression (at eye-opening and in adulthood) in two brain regions mediating executive functions and memory (hippocampus and prefrontal cortex, PFC). Compared to control mice, WT offspring deprived of 6'SL during lactation exhibited consistent alterations in all cognitive functions addressed, hippocampal electrophysiology, and in pathways regulating the serotonergic system (identified through gut microbiota and plasma metabolomics). These were associated with a site- (PFC) and time-specific (eye-opening) reduced expression of genes involved in central nervous system development. Our data suggest that 6'SL in maternal milk adjusts cognitive development through a short-term upregulation of genes modulating neuronal patterning in the PFC.
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http://dx.doi.org/10.1038/s41380-021-01054-9DOI Listing
March 2021

Large-scale association analyses identify host factors influencing human gut microbiome composition.

Nat Genet 2021 02 18;53(2):156-165. Epub 2021 Jan 18.

Department of Twin Research & Genetic Epidemiology, King's College London, London, UK.

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 < 5 × 10) threshold. One locus, the lactase (LCT) gene locus, reached study-wide significance (genome-wide association study signal: P = 1.28 × 10), and it showed an age-dependent association with Bifidobacterium abundance. Other associations were suggestive (1.95 × 10 < P < 5 × 10) but enriched for taxa showing high heritability and for genes expressed in the intestine and brain. A phenome-wide association study and Mendelian randomization identified enrichment of microbiome trait loci in the metabolic, nutrition and environment domains and suggested the microbiome might have causal effects in ulcerative colitis and rheumatoid arthritis.
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http://dx.doi.org/10.1038/s41588-020-00763-1DOI Listing
February 2021

Attention-deficit/hyperactivity disorder symptoms and dietary habits in adulthood: A large population-based twin study in Sweden.

Am J Med Genet B Neuropsychiatr Genet 2020 12 7;183(8):475-485. Epub 2020 Oct 7.

School of Medical Sciences, Örebro University, Örebro, Sweden.

Associations between adult attention-deficit/hyperactivity disorder (ADHD) symptoms and dietary habits have not been well established and the underlying mechanisms remain unclear. We explored these associations using a Swedish population-based twin study with 17,999 individuals aged 20-47 years. We estimated correlations between inattention and hyperactivity/impulsivity with dietary habits and fitted twin models to determine the genetic and environmental contributions. Dietary habits were defined as (a) consumption of food groups, (b) consumption of food items rich in particular macronutrients, and (c) healthy and unhealthy dietary patterns. At the phenotypic level, inattention was positively correlated with seafood, high-fat, high-sugar, high-protein food consumptions, and unhealthy dietary pattern, with correlation coefficients ranging from 0.03 (95%CI: 0.01, 0.05) to 0.13 (95% CI: 0.11, 0.15). Inattention was negatively correlated with fruits, vegetables consumptions and healthy dietary pattern, with correlation coefficients ranging from -0.06 (95%CI: -0.08, -0.04) to -0.07 (95%CI: -0.09, -0.05). Hyperactivity/impulsivity and dietary habits showed similar but weaker patterns compared to inattention. All associations remained stable across age, sex and socioeconomic status. Nonshared environmental effects contributed substantially to the correlations of inattention (56-60%) and hyperactivity/impulsivity (63-80%) with dietary habits. The highest and lowest genetic correlations were between inattention and high-sugar food (r = .16, 95% CI: 0.07, 0.25), and between hyperactivity/impulsivity and unhealthy dietary pattern (r = .05, 95% CI: -0.05, 0.14), respectively. We found phenotypic and etiological overlap between ADHD and dietary habits, although these associations were weak. Our findings contribute to a better understanding of common etiological pathways between ADHD symptoms and various dietary habits.
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http://dx.doi.org/10.1002/ajmg.b.32825DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7702140PMC
December 2020

Diet quality, stress and common mental health problems: A cohort study of 121,008 adults.

Clin Nutr 2021 03 30;40(3):901-906. Epub 2020 Jun 30.

University of Groningen, University Medical Center Groningen, Interdisciplinary Center Psychopathology and Emotion Regulation (LJSS, CAH), Hanzeplein 1, Groningen, 9700 RB, the Netherlands.

Background & Aims: Overall diet quality may partially mediate the detrimental effects of stress and neuroticism on common mental health problems: stressed and/or neurotic individuals may be more prone to unhealthy dietary habits, which in turn may contribute to depression and anxiety. Lifestyle interventions for depressed, anxious or at-risk individuals hinge on this idea, but evidence to support such pathway is missing. Here, we aim to prospectively evaluate the role of overall diet quality in common pathways to developing depression and anxiety.

Methods: At baseline, N = 121,008 individuals from the general population (age 18-93) completed an extensive food frequency questionnaire, based on which overall diet quality was estimated. Participants also reported on two established risk factors for mental health problems, i.e. past-year stress exposure (long-term difficulties, stressful life-events) and four neuroticism traits (anger-hostility, self-consciousness, impulsivity, vulnerability). Depression and anxiety were assessed at baseline and follow-up (n = 65,342, +3.6 years). Overall diet quality was modeled as a mediator in logistic regression models predicting the development of depression and anxiety from common risk factors.

Results: High stress and high neuroticism scores were - albeit weakly - associated with poorer diet quality. Poor diet quality, in turn, did not predict mental health problems. Overall diet quality did not mediate the relationship between stress/neuroticism and common mental health problems: effects of stress, neuroticism and stress-by-neuroticism interactions on mental health problems at follow-up consisted entirely of direct effects (98.6%-100%).

Conclusions: Diet quality plays no mediating role in two established pathways to common mental health problems. As overall diet quality was reduced in stressed and neurotic individuals, these groups may benefit from dietary interventions. However, such interventions are unlikely to prevent the onset or recurrence of depression and anxiety.
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http://dx.doi.org/10.1016/j.clnu.2020.06.016DOI Listing
March 2021

Identification and validation of risk factors for antisocial behaviour involving police.

Psychiatry Res 2020 09 12;291:113208. Epub 2020 Jun 12.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, the Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, Route 836, room 4.84, Nijmegen 6525, GA, the Netherlands.

Adult antisocial behaviour has precursors in childhood and adolescence and is most successfully treated using childhood interventions. The aim of this study was to identify and validate robust risk factors for antisocial behaviour involving police contact in a data-driven, hypothesis-free framework. Antisocial behavior involving police contact (20/25% incidence) as well as 554 other behavioural and environmental measures were assessed in the longitudinal general population Estonian Children Personality Behaviour and Health Study sample (n=872). The strongest risk factors for antisocial behaviour included past substance use disorder, gender, aggressive mode of action upon provocation, and concentration difficulties and physical fighting in school at age 15 years. Prediction using the selected variables for both methods in the other, unseen cohort resulted in an area under the receiver operating characteristics curve of 0.78-0.84. Our work confirms known risk factors for antisocial behaviour as well as identifies novel specific risk factors. Together, these provide good predictive power in an unseen cohort. Our identification and validation of risk factors for antisocial behaviour can aid early intervention for at-risk individuals.
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http://dx.doi.org/10.1016/j.psychres.2020.113208DOI Listing
September 2020

A two arm randomized controlled trial comparing the short and long term effects of an elimination diet and a healthy diet in children with ADHD (TRACE study). Rationale, study design and methods.

BMC Psychiatry 2020 05 27;20(1):262. Epub 2020 May 27.

Karakter, Child and Adolescent Psychiatry, Reinier Postlaan 12, 6525, GC, Nijmegen, the Netherlands.

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.
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http://dx.doi.org/10.1186/s12888-020-02576-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7251686PMC
May 2020

Structural brain alterations and their association with cognitive function and symptoms in Attention-deficit/Hyperactivity Disorder families.

Neuroimage Clin 2020 23;27:102273. Epub 2020 Apr 23.

Department of Psychology, Georgia State University, USA; Neuroscience Institute, Georgia State University, USA. Electronic address:

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.
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http://dx.doi.org/10.1016/j.nicl.2020.102273DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7210582PMC
March 2021

Shared genetic background between children and adults with attention deficit/hyperactivity disorder.

Neuropsychopharmacology 2020 09 12;45(10):1617-1626. Epub 2020 Apr 12.

Department of Genetics, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Porto Alegre, Brazil.

Attention deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder characterized by age-inappropriate symptoms of inattention, impulsivity, and hyperactivity that persist into adulthood in the majority of the diagnosed children. Despite several risk factors during childhood predicting the persistence of ADHD symptoms into adulthood, the genetic architecture underlying the trajectory of ADHD over time is still unclear. We set out to study the contribution of common genetic variants to the risk for ADHD across the lifespan by conducting meta-analyses of genome-wide association studies on persistent ADHD in adults and ADHD in childhood separately and jointly, and by comparing the genetic background between them in a total sample of 17,149 cases and 32,411 controls. Our results show nine new independent loci and support a shared contribution of common genetic variants to ADHD in children and adults. No subgroup heterogeneity was observed among children, while this group consists of future remitting and persistent individuals. We report similar patterns of genetic correlation of ADHD with other ADHD-related datasets and different traits and disorders among adults, children, and when combining both groups. These findings confirm that persistent ADHD in adults is a neurodevelopmental disorder and extend the existing hypothesis of a shared genetic architecture underlying ADHD and different traits to a lifespan perspective.
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http://dx.doi.org/10.1038/s41386-020-0664-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7419307PMC
September 2020

Gut microbiota from persons with attention-deficit/hyperactivity disorder affects the brain in mice.

Microbiome 2020 04 1;8(1):44. Epub 2020 Apr 1.

Department of Anatomy, Donders Institute for Brain, Cognition & Behaviour, Preclinical Imaging Centre PRIME, Radboud University Medical Center, Geert Grooteplein noord 21, 6525 EZ, Nijmegen, The Netherlands.

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.
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http://dx.doi.org/10.1186/s40168-020-00816-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7114819PMC
April 2020

The genetic architecture of the human cerebral cortex.

Science 2020 03;367(6484)

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
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http://dx.doi.org/10.1126/science.aay6690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7295264PMC
March 2020

Investigating the Gut Microbiota Composition of Individuals with Attention-Deficit/Hyperactivity Disorder and Association with Symptoms.

Microorganisms 2020 Mar 13;8(3). Epub 2020 Mar 13.

Department of Psychiatry, Radboudumc, Donders Institute for Brain, Cognition and Behaviour, 6525 GA Nijmegen, The Netherlands.

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental disorder. Given the growing evidence of gut microbiota being involved in psychiatric (including neurodevelopmental) disorders, we aimed to identify differences in gut microbiota composition between participants with ADHD and controls and to investigate the role of the microbiota in inattention and hyperactivity/impulsivity. Fecal samples were collected from 107 participants (N = 42; N = 50; N = 15; range age: 13-29 years). The relative quantification of bacterial taxa was done using 16S ribosomal RNA gene amplicon sequencing. Beta-diversity revealed significant differences in bacterial composition between participants with ADHD and healthy controls, which was also significant for inattention, but showing a trend in case of hyperactivity/impulsivity only. Ten genera showed nominal differences ( < 0.05) between both groups, of which seven genera were tested for their association with ADHD symptom scores (adjusting for age, sex, body mass index, time delay between feces collection and symptoms assessment, medication use, and family relatedness). Our results show that variation of a genus from the family () is associated (after multiple testing correction) with inattention symptoms and support the potential role of gut microbiota in ADHD pathophysiology.
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http://dx.doi.org/10.3390/microorganisms8030406DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7143990PMC
March 2020

Treating impulsivity with probiotics in adults (PROBIA): study protocol of a multicenter, double-blind, randomized, placebo-controlled trial.

Trials 2020 Feb 11;21(1):161. Epub 2020 Feb 11.

Department of Psychiatry, Hospital Universitari Vall d'Hebron, Barcelona, Catalonia, Spain.

Background: Impulsivity and compulsivity are related to emotional and social maladjustment and often underlie psychiatric disorders. Recently, alterations in microbiota composition have been shown to have implications for brain development and social behavior via the microbiota-gut-brain axis. However, the exact mechanisms are not fully identified. Recent evidence suggests the modulatory effect of synbiotics on gut microbiota and the contribution of these agents in ameliorating symptoms of many psychiatric diseases. To date, no randomized controlled trial has been performed to establish the feasibility and efficacy of this intervention targeting the reduction of impulsivity and compulsivity. We hypothesize that supplementation with synbiotics may be an effective treatment in adults with high levels of impulsivity and/or compulsivity.

Methods/design: This is a prospective, multicenter, double-blind, randomized controlled trial with two arms: treatment with a synbiotic formula versus placebo treatment. The primary outcome is the response rate at the end of the placebo-controlled phase (response defined as a Clinical Global Impression-Improvement Scale score of 1 or 2 = very much improved or much improved, plus a reduction in the Affective Reactivity Index total score of at least 30% compared with baseline). A total of 180 participants with highly impulsive behavior and a diagnosis of attention deficit/hyperactivity disorder (ADHD) and/or borderline personality disorder, aged 18-65 years old, will be screened at three study centers. Secondary outcome measures, including changes in general psychopathology, ADHD symptoms, neurocognitive function, somatic parameters, physical activity, nutritional intake, and health-related quality of life, will be explored at assessments before, during, and at the end of the intervention. The effect of the intervention on genetics, microbiota, and several blood biomarkers will also be assessed. Gastrointestinal symptoms and somatic complaints will additionally be explored at 1-week follow-up.

Discussion: This is the first randomized controlled trial to determine the effects of supplementation with synbiotics on reducing impulsive and compulsive behavior. This clinical trial can contribute to explaining the mechanisms involved in the crosstalk between the intestinal microbiome and the brain. If effects can be established by reducing impulsive and compulsive behavior, new cost-effective treatments might become available to these patients.

Trial Registration: ClinicalTrials.gov, NCT03495375. Registered on 26 February 2018.
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http://dx.doi.org/10.1186/s13063-019-4040-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7014653PMC
February 2020

Contribution of Intellectual Disability-Related Genes to ADHD Risk and to Locomotor Activity in .

Am J Psychiatry 2020 06 12;177(6):526-536. Epub 2020 Feb 12.

Department of Human Genetics (Klein, Singgih, van Rens, Mota, Castells-Nobau, Brunner, Arias-Vasquez, Schenck, van der Voet, Franke), Department of Psychiatry (Mota, Arias-Vasquez, Franke), and Department for Health Evidence (Kiemeney), Radboud University Medical Center and Donders Institute for Brain, Cognition, and Behavior, Nijmegen, the Netherlands; Department of Biomedicine and Center for Integrative Sequencing (iSEQ), Aarhus University, Aarhus, Denmark (Demontis, Børglum); and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum).

Objective: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using .

Methods: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits.

Results: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were , , and . Performing functional characterization of the two evolutionarily conserved genes in , the authors found that their knockdown in dopaminergic () and circadian neurons () resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype.

Conclusions: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified , , and as novel ADHD candidate genes. Characterization in suggests that and contribute to ADHD-related behavior through distinct neural substrates.
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http://dx.doi.org/10.1176/appi.ajp.2019.18050599DOI Listing
June 2020

Cross-disorder genetic analyses implicate dopaminergic signaling as a biological link between Attention-Deficit/Hyperactivity Disorder and obesity measures.

Neuropsychopharmacology 2020 06 2;45(7):1188-1195. Epub 2020 Jan 2.

Department of Human Genetics, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Nijmegen, The Netherlands.

Attention-Deficit/Hyperactivity Disorder (ADHD) and obesity are frequently comorbid, genetically correlated, and share brain substrates. The biological mechanisms driving this association are unclear, but candidate systems, like dopaminergic neurotransmission and circadian rhythm, have been suggested. Our aim was to identify the biological mechanisms underpinning the genetic link between ADHD and obesity measures and investigate associations of overlapping genes with brain volumes. We tested the association of dopaminergic and circadian rhythm gene sets with ADHD, body mass index (BMI), and obesity (using GWAS data of N = 53,293, N = 681,275, and N = 98,697, respectively). We then conducted genome-wide ADHD-BMI and ADHD-obesity gene-based meta-analyses, followed by pathway enrichment analyses. Finally, we tested the association of ADHD-BMI overlapping genes with brain volumes (primary GWAS data N = 10,720-10,928; replication data N = 9428). The dopaminergic gene set was associated with both ADHD (P = 5.81 × 10) and BMI (P = 1.63 × 10); the circadian rhythm was associated with BMI (P = 1.28 × 10). The genome-wide approach also implicated the dopaminergic system, as the Dopamine-DARPP32 Feedback in cAMP Signaling pathway was enriched in both ADHD-BMI and ADHD-obesity results. The ADHD-BMI overlapping genes were associated with putamen volume (P = 7.7 × 10; replication data P = 3.9 × 10)-a brain region with volumetric reductions in ADHD and BMI and linked to inhibitory control. Our findings suggest that dopaminergic neurotransmission, partially through DARPP-32-dependent signaling and involving the putamen, is a key player underlying the genetic overlap between ADHD and obesity measures. Uncovering shared etiological factors underlying the frequently observed ADHD-obesity comorbidity may have important implications in terms of prevention and/or efficient treatment of these conditions.
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http://dx.doi.org/10.1038/s41386-019-0592-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7234984PMC
June 2020

Screening for drugs to reduce zebrafish aggression identifies caffeine and sildenafil.

Eur Neuropsychopharmacol 2020 01 1;30:17-29. Epub 2019 Nov 1.

Department of Neuroscience, Psychology and Behaviour, College of Life Sciences, University of Leicester, Leicester LE1 7RH, UK. Electronic address:

Although aggression is a common symptom of psychiatric disorders the drugs available to treat it are non-specific and can have unwanted side effects. In this study we have used a behavioural platform in a phenotypic screen to identify drugs that can reduce zebrafish aggression without affecting locomotion. In a three tier screen of ninety-four drugs we discovered that caffeine and sildenafil can selectively reduce aggression. Caffeine also decreased attention and increased impulsivity in the 5-choice serial reaction time task whereas sildenafil showed the opposite effect. Imaging studies revealed that both caffeine and sildenafil are active in the zebrafish brain, with prominent activation of the thalamus and cerebellum evident. They also interact with 5-HT neurotransmitter signalling. In summary, we have demonstrated that juvenile zebrafish are a suitable model to screen for novel drugs to reduce aggression, with the potential to uncover the neural circuits and signalling pathways that mediate such behavioural effects.
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http://dx.doi.org/10.1016/j.euroneuro.2019.10.005DOI Listing
January 2020

Genetic architecture of subcortical brain structures in 38,851 individuals.

Nat Genet 2019 11 21;51(11):1624-1636. Epub 2019 Oct 21.

Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, USA.

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.
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http://dx.doi.org/10.1038/s41588-019-0511-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7055269PMC
November 2019

Modulation of cognitive flexibility by reward and punishment in BALB/cJ and BALB/cByJ mice.

Behav Brain Res 2020 01 15;378:112294. Epub 2019 Oct 15.

Department of Cognitive Neuroscience, Radboud University Medical Center, Donders Institute for Brain, Cognition and Behaviour, Kapittelweg 29, 6525 EN, Nijmegen, The Netherlands.

Learning from feedback is one of the key mechanisms within cognitive flexibility, which is needed to react swiftly to constantly changing environments. The motivation to change behavior is highly dependent on the expectancy of positive (reward) or negative (punishment) feedback. Individuals with conduct disorder (CD) with high callous unemotional traits show decreased sensitivity to negative feedback and increased reward seeking. Previous studies have modeled traits associated with CD (i.e. heightened aggression and anti-social behavior) in BALB/cJ mice (compared to the BALB/cByJ mouse as controls). Based on these findings, we hypothesized reduced negative feedback-related cognitive flexibility to be present in BALB/cJ mice. The effect of negative feedback and reward sensitivity on cognitive flexibility in BALB/cJ and BALB/cByJ mice was examined in a reversal learning paradigm. BALB/cJ mice were more flexible in the acquisition of new contingencies under rewarding conditions compared to BALB/cByJ mice, while the presence of an aversive punishing stimulus decreased their learning performance. Additionally, BALB/cJ mice needed more correction trials to reach the reversal learning criterion. This was accompanied by a higher rate of perseverance, which could represent impaired error detection. The addition of a second punishment enhanced punishment sensitivity in BALB/cJ mice. In contrast, the performance of the BALB/cByJ mice was not affected by additional negative feedback. Taken together, the BALB/cJ can be considered to be less sensitive to learn from negative feedback and therefore may be a useful model to further characterize molecular and neural underpinnings of callous unemotional traits in CD.
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http://dx.doi.org/10.1016/j.bbr.2019.112294DOI Listing
January 2020

The Role of the Gut-Brain Axis in Attention-Deficit/Hyperactivity Disorder.

Gastroenterol Clin North Am 2019 09 2;48(3):407-431. Epub 2019 Jul 2.

Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands; Department of Psychiatry, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Geert Grooteplein Zuid 10, 6525 GA, Nijmegen, The Netherlands.

Genetic and environmental factors play a role in the cause and development of attention-deficit/hyperactivity disorder (ADHD). Recent studies have suggested an important role of the gut-brain axis (GBA) and intestinal microbiota in modulating the risk of ADHD. Here, the authors provide a brief overview of the clinical and biological picture of ADHD and how the GBA could be involved in its cause. They discuss key biological mechanisms involved in the GBA and how these may increase the risk of developing ADHD. Understanding these mechanisms may help to characterize novel treatment options via identification of disease biomarkers.
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http://dx.doi.org/10.1016/j.gtc.2019.05.001DOI Listing
September 2019

Multi-Site Meta-Analysis of Morphometry.

IEEE/ACM Trans Comput Biol Bioinform 2019 Sep-Oct;16(5):1508-1514. Epub 2019 May 23.

Genome-wide association studies (GWAS) link full genome data to a handful of traits. However, in neuroimaging studies, there is an almost unlimited number of traits that can be extracted for full image-wide big data analyses. Large populations are needed to achieve the necessary power to detect statistically significant effects, emphasizing the need to pool data across multiple studies. Neuroimaging consortia, e.g., ENIGMA and CHARGE, are now analyzing MRI data from over 30,000 individuals. Distributed processing protocols extract harmonized features at each site, and pool together only the cohort statistics using meta analysis to avoid data sharing. To date, such MRI projects have focused on single measures such as hippocampal volume, yet voxelwise analyses (e.g., tensor-based morphometry; TBM) may help better localize statistical effects. This can lead to $10^{13}$1013 tests for GWAS and become underpowered. We developed an analytical framework for multi-site TBM by performing multi-channel registration to cohort-specific templates. Our results highlight the reliability of the method and the added power over alternative options while preserving single site specificity and opening the doors for well-powered image-wide genome-wide discoveries.
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http://dx.doi.org/10.1109/TCBB.2019.2914905DOI Listing
March 2020

Genetic Markers of ADHD-Related Variations in Intracranial Volume.

Am J Psychiatry 2019 03;176(3):228-238

The Department of Human Genetics, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Klein, Bralten, Roth Mota, Arias-Vasquez, Franke); University Medical Center Utrecht, UMC Utrecht Brain Center, Department of Psychiatry, Utrecht, the Netherlands (Klein); the Analytic and Translational Genetics Unit, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Boston (Walters, Neale); Program in Medical and Population Genetics (Walters) and Stanley Center for Psychiatric Research, Broad Institute of Harvard and MIT, Cambridge, Mass (Walters, Neale); the Department of Biomedicine and the Center for Integrative Sequencing, Aarhus University, Aarhus, Denmark (Demontis, Mattheisen, Børglum); the Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Denmark (Demontis, Børglum); the Department of Genetics and the Neuroscience Center, University of North Carolina, Chapel Hill (Stein); the Imaging Genetics Center, USC Mark and Mary Stevens Neuroimaging and Informatics Institute, Keck School of Medicine, University of Southern California, Los Angeles (Hibar, Thompson); the Department of Epidemiology and the Department of Radiology and Nuclear Medicine, Erasmus Medical Center, Rotterdam, the Netherlands (Adams); the Department of Psychiatry and the Research Institute, Hospital for Sick Children, University of Toronto, Toronto (Schachar); the Department of Child and Adolescent Psychiatry, Institute of Psychiatry, Psychology, and Neuroscience, King's College London (Sonuga-Barke); the Department of Psychiatry, Psychosomatics and Psychotherapy, University of Wuerzburg, Wuerzburg, Germany (Mattheisen); the Department of Clinical Neuroscience, Center for Psychiatric Research, Karolinska Institute, Stockholm (Mattheisen); Stockholm Health Care Services, Stockholm County Council, Stockholm (Mattheisen); the Department of Neurology, Keck School of Medicine, University of Southern California, Los Angeles (Thompson); the Quantitative Genetics Laboratory, QIMR Berghofer Medical Research Institute, Brisbane, Australia (Medland); the Department of Psychiatry and the Department of Neuroscience and Physiology, SUNY Upstate Medical University, Syracuse, N.Y. (Faraone); the K.G. Jebsen Center for Neuropsychiatric Disorders, University of Bergen, Bergen, Norway (Faraone); and the Department of Psychiatry, Donders Institute for Brain, Cognition, and Behavior, Radboud University Medical Center, Nijmegen, the Netherlands (Roth Mota, Arias-Vasquez, Franke).

Objective: Attention deficit hyperactivity disorder (ADHD) is a common and highly heritable neurodevelopmental disorder with a complex pathophysiology. Intracranial volume (ICV) and volumes of the nucleus accumbens, amygdala, caudate nucleus, hippocampus, and putamen are smaller in people with ADHD compared with healthy individuals. The authors investigated the overlap between common genetic variation associated with ADHD risk and these brain volume measures to identify underlying biological processes contributing to the disorder.

Methods: The authors combined genome-wide association results from the largest available studies of ADHD (N=55,374) and brain volumes (N=11,221-24,704), using a set of complementary methods to investigate overlap at the level of global common variant genetic architecture and at the single variant level.

Results: Analyses revealed a significant negative genetic correlation between ADHD and ICV (r=-0.22). Meta-analysis of single variants revealed two significant loci of interest associated with both ADHD risk and ICV; four additional loci were identified for ADHD and volumes of the amygdala, caudate nucleus, and putamen. Exploratory gene-based and gene-set analyses in the ADHD-ICV meta-analytic data showed association with variation in neurite outgrowth-related genes.

Conclusions: This is the first genome-wide study to show significant genetic overlap between brain volume measures and ADHD, both on the global and the single variant level. Variants linked to smaller ICV were associated with increased ADHD risk. These findings can help us develop new hypotheses about biological mechanisms by which brain structure alterations may be involved in ADHD disease etiology.
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http://dx.doi.org/10.1176/appi.ajp.2018.18020149DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7780894PMC
March 2019

Epigenetic signature for attention-deficit/hyperactivity disorder: identification of miR-26b-5p, miR-185-5p, and miR-191-5p as potential biomarkers in peripheral blood mononuclear cells.

Neuropsychopharmacology 2019 04 19;44(5):890-897. Epub 2018 Dec 19.

Psychiatric Genetics Unit, Group of Psychiatry, Mental Health and Addiction, Vall d'Hebron Research Institute (VHIR), Universitat Autònoma de Barcelona, Barcelona, Catalonia, Spain.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most prevalent neurodevelopmental disorders in childhood and persists into adulthood in 40-65% of cases. Given the polygenic and heterogeneous architecture of the disorder and the limited overlap between genetic studies, there is a growing interest in epigenetic mechanisms, such as microRNAs, that modulate gene expression and may contribute to the phenotype. We attempted to clarify the role of microRNAs in ADHD at a molecular level through the first genome-wide integrative study of microRNA and mRNA profiles in peripheral blood mononuclear cells of medication-naive individuals with ADHD and healthy controls. We identified 79 microRNAs showing aberrant expression levels in 56 ADHD cases and 69 controls, with three of them, miR-26b-5p, miR-185-5p, and miR-191-5p, being highly predictive for diagnostic status in an independent dataset of 44 ADHD cases and 46 controls. Investigation of downstream microRNA-mediated mechanisms underlying the disorder, which was focused on differentially expressed, experimentally validated target genes of the three highly predictive microRNAs, provided evidence for aberrant myo-inositol signaling in ADHD and indicated an enrichment of genes involved in neurological disease and psychological disorders. Our comprehensive study design reveals novel microRNA-mRNA expression profiles aberrant in ADHD, provides novel insights into microRNA-mediated mechanisms contributing to the disorder, and highlights promising candidate peripheral biomarkers.
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http://dx.doi.org/10.1038/s41386-018-0297-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6461896PMC
April 2019
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