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1.
Ann N Y Acad Sci ; 2024 Aug 16.
Artigo em Inglês | MEDLINE | ID: mdl-39150983

RESUMO

Impulsivity has been proposed to have an impact on glycemic dysregulation. However, it remains uncertain whether an unfavorable glycemic status could also contribute to an increase in impulsivity levels. This study aims to analyze associations of baseline and time-varying glycemic status with 3-year time-varying impulsivity in older adults at high risk of cardiovascular disease. A 3-year prospective cohort design was conducted within the PREDIMED-Plus-Cognition substudy. The total population includes 487 participants (mean age = 65.2 years; female = 50.5%) with overweight or obesity and metabolic syndrome. Insulin resistance (HOMA-IR), glycated hemoglobin (HbA1c), presence of type 2 diabetes mellitus, and type 2 diabetes control were evaluated. Impulsivity was measured using the Impulsive Behavior Scale questionnaire and various cognitive measurements. Impulsivity z-scores were generated to obtain Global, Trait, and Behavioral Impulsivity domains. Linear mixed models were used to study the longitudinal associations across baseline, 1-year, and 3-year follow-up visits. HOMA-IR was not significantly related to impulsivity. Participants with higher HbA1c levels, type 2 diabetes, and poor control of diabetes showed positive associations with the Global Impulsivity domain over time, and those with higher HbA1c levels were further related to increases in the Trait and Behavioral Impulsivity domains over the follow-up visits. These results suggest a potential positive feedback loop between impulsivity and glycemic-related dysregulation.

2.
bioRxiv ; 2024 Aug 06.
Artigo em Inglês | MEDLINE | ID: mdl-39149253

RESUMO

Background: Inter-individual variability in neurobiological and clinical characteristics in mental illness is often overlooked by classical group-mean case-control studies. Studies using normative modelling to infer person-specific deviations of grey matter volume have indicated that group means are not representative of most individuals. The extent to which this variability is present in white matter morphometry, which is integral to brain function, remains unclear. Methods: We applied Warped Bayesian Linear Regression normative models to T1-weighted magnetic resonance imaging data and mapped inter-individual variability in person-specific white matter volume deviations in 1,294 cases (58% male) diagnosed with one of six disorders (attention-deficit/hyperactivity, autism, bipolar, major depressive, obsessive-compulsive and schizophrenia) and 1,465 matched controls (54% male) recruited across 25 scan sites. We developed a framework to characterize deviation heterogeneity at multiple spatial scales, from individual voxels, through inter-regional connections, specific brain regions, and spatially extended brain networks. Results: The specific locations of white matter volume deviations were highly heterogeneous across participants, affecting the same voxel in fewer than 8% of individuals with the same diagnosis. For autism and schizophrenia, negative deviations (i.e., areas where volume is lower than normative expectations) aggregated into common tracts, regions and large-scale networks in up to 35% of individuals. Conclusions: The prevalence of white matter volume deviations was lower than previously observed in grey matter, and the specific location of these deviations was highly heterogeneous when considering voxel-wise spatial resolution. Evidence of aggregation within common pathways and networks was apparent in schizophrenia and autism but not other disorders.

3.
Eur Neuropsychopharmacol ; 88: 21-29, 2024 Aug 08.
Artigo em Inglês | MEDLINE | ID: mdl-39121711

RESUMO

Attention-deficit/hyperactivity disorder (ADHD) is a common neurodevelopmental condition that persists into adulthood in the majority of individuals. While the gut-microbiome seems to be relevant for ADHD, the few publications on gut-microbial alterations in ADHD are inconsistent, in the investigated phenotypes, sequencing method/region, preprocessing, statistical approaches, and findings. To identify gut-microbiome alterations in adult ADHD, robust across studies and statistical approaches, we harmonized bioinformatic pipelines and analyses of raw 16S rRNA sequencing data from four adult ADHD case-control studies (NADHD=312, NNoADHD=305). We investigated diversity and differential abundance of selected genera (logistic regression and ANOVA-like Differential Expression tool), corrected for age and sex, and meta-analyzed the study results. Converging results were investigated for association with hyperactive/impulsive and inattentive symptoms across all participants. Beta diversity was associated with ADHD diagnosis but showed significant heterogeneity between cohorts, despite harmonized analyses. Several genera were robustly associated with adult ADHD; e.g., Ruminococcus_torques_group (LogOdds=0.17, pfdr=4.42 × 10-2), which was more abundant in adults with ADHD, and Eubacterium_xylanophilum_group (LogOdds= -0.12, pfdr=6.9 × 10-3), which was less abundant in ADHD. Ruminococcus_torques_group was further associated with hyperactivity/impulsivity symptoms and Eisenbergiella with inattention and hyperactivity/impulsivity (pfdr<0.05). The literature points towards a role of these genera in inflammatory processes. Irreproducible results in the field of gut-microbiota research, due to between study heterogeneity and small sample sizes, stress the need for meta-analytic approaches and large sample sizes. While we robustly identified genera associated with adult ADHD, that might overall be considered beneficial or risk-conferring, functional studies are needed to shed light on these properties.

4.
Hum Brain Mapp ; 45(10): e26768, 2024 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-38949537

RESUMO

Structural neuroimaging data have been used to compute an estimate of the biological age of the brain (brain-age) which has been associated with other biologically and behaviorally meaningful measures of brain development and aging. The ongoing research interest in brain-age has highlighted the need for robust and publicly available brain-age models pre-trained on data from large samples of healthy individuals. To address this need we have previously released a developmental brain-age model. Here we expand this work to develop, empirically validate, and disseminate a pre-trained brain-age model to cover most of the human lifespan. To achieve this, we selected the best-performing model after systematically examining the impact of seven site harmonization strategies, age range, and sample size on brain-age prediction in a discovery sample of brain morphometric measures from 35,683 healthy individuals (age range: 5-90 years; 53.59% female). The pre-trained models were tested for cross-dataset generalizability in an independent sample comprising 2101 healthy individuals (age range: 8-80 years; 55.35% female) and for longitudinal consistency in a further sample comprising 377 healthy individuals (age range: 9-25 years; 49.87% female). This empirical examination yielded the following findings: (1) the accuracy of age prediction from morphometry data was higher when no site harmonization was applied; (2) dividing the discovery sample into two age-bins (5-40 and 40-90 years) provided a better balance between model accuracy and explained age variance than other alternatives; (3) model accuracy for brain-age prediction plateaued at a sample size exceeding 1600 participants. These findings have been incorporated into CentileBrain (https://centilebrain.org/#/brainAGE2), an open-science, web-based platform for individualized neuroimaging metrics.


Assuntos
Envelhecimento , Encéfalo , Imageamento por Ressonância Magnética , Humanos , Adolescente , Feminino , Idoso , Adulto , Criança , Adulto Jovem , Masculino , Encéfalo/diagnóstico por imagem , Encéfalo/anatomia & histologia , Encéfalo/crescimento & desenvolvimento , Idoso de 80 Anos ou mais , Pré-Escolar , Pessoa de Meia-Idade , Envelhecimento/fisiologia , Imageamento por Ressonância Magnética/métodos , Neuroimagem/métodos , Neuroimagem/normas , Tamanho da Amostra
5.
Artigo em Inglês | MEDLINE | ID: mdl-39016115

RESUMO

Genome-wide association studies (GWAS) have provided valuable insights into the genetic basis of neuropsychiatric disorders and highlighted their complexity. Careful consideration of the polygenicity and complex genetic architecture could aid in the understanding of the underlying brain mechanisms. We introduce an innovative approach to polygenic scoring, utilizing imaging-derived phenotypes (IDPs) to predict a clinical phenotype. We leveraged IDP GWAS data from the UK Biobank, to create polygenic imaging-derived scores (PIDSs). As a proof-of-concept, we assessed genetic variations in brain structure between individuals with ADHD and unaffected controls across three NeuroIMAGE waves (n = 954). Out of the 94 PIDS, 72 exhibited significant associations with their corresponding IDPs in an independent sample. Notably, several global measures, including cerebellum white matter, cerebellum cortex, and cerebral white matter, displayed substantial variance explained for their respective IDPs, ranging from 3% to 5.7%. Conversely, the associations between each IDP and the clinical ADHD phenotype were relatively weak. These findings highlight the growing power of GWAS in structural neuroimaging traits, enabling the construction of polygenic scores that accurately reflect the underlying polygenic architecture. However, to establish robust connections between PIDS and behavioral or clinical traits such as ADHD, larger samples are needed. Our novel approach to polygenic risk scoring offers a valuable tool for researchers in the field of psychiatric genetics.

6.
Nutrients ; 16(14)2024 Jul 09.
Artigo em Inglês | MEDLINE | ID: mdl-39064617

RESUMO

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.


Assuntos
Agressão , Transtorno do Deficit de Atenção com Hiperatividade , Dieta , Microbioma Gastrointestinal , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/microbiologia , Adulto , Masculino , Feminino , Fezes/microbiologia , Adulto Jovem , Pessoa de Meia-Idade , Ingestão de Energia
7.
Dev Cogn Neurosci ; 67: 101403, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38852381

RESUMO

Our society faces a great diversity of opportunities for youth. The 10-year Growing Up Together in Society (GUTS) program has the long-term goal to understand which combination of measures best predict societal trajectories, such as school success, mental health, well-being, and developing a sense of belonging in society. Our leading hypothesis is that self-regulation is key to how adolescents successfully navigate the demands of contemporary society. We aim to test these questions using socio-economic, questionnaire (including experience sampling methods), behavioral, brain (fMRI, sMRI, EEG), hormonal, and genetic measures in four large cohorts including adolescents and young adults. Two cohorts are designed as test and replication cohorts to test the developmental trajectory of self-regulation, including adolescents of different socioeconomic status thereby bridging individual, family, and societal perspectives. The third cohort consists of an entire social network to examine how neural and self-regulatory development influences and is influenced by whom adolescents and young adults choose to interact with. The fourth cohort includes youth with early signs of antisocial and delinquent behavior to understand patterns of societal development in individuals at the extreme ends of self-regulation and societal participation, and examines pathways into and out of delinquency. We will complement the newly collected cohorts with data from existing large-scale population-based and case-control cohorts. The study is embedded in a transdisciplinary approach that engages stakeholders throughout the design stage, with a strong focus on citizen science and youth participation in study design, data collection, and interpretation of results, to ensure optimal translation to youth in society.


Assuntos
Autocontrole , Humanos , Adolescente , Adulto Jovem , Masculino , Feminino , Encéfalo/crescimento & desenvolvimento , Estudos de Coortes , Adulto , Desenvolvimento do Adolescente/fisiologia
8.
medRxiv ; 2024 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-38826220

RESUMO

The brain's default mode network (DMN) plays a role in social cognition, with altered DMN function being associated with social impairments across various neuropsychiatric disorders. In the present study, we examined the genetic relationship between sociability and DMN-related resting-state functional magnetic resonance imaging (rs-fMRI) traits. To this end, we used genome-wide association summary statistics for sociability and 31 activity and 64 connectivity DMN-related rs-fMRI traits (N=34,691-342,461). First, we examined global and local genetic correlations between sociability and the rs-fMRI traits. Second, to assess putatively causal relationships between the traits, we conducted bi-directional Mendelian randomisation (MR) analyses. Finally, we prioritised genes influencing both sociability and rs-fMRI traits by combining three methods: gene-expression eQTL MR analyses, the CELLECT framework using single-nucleus RNA-seq data, and network propagation in the context of a protein-protein interaction network. Significant local genetic correlations were found between sociability and two rs-fMRI traits, one representing spontaneous activity within the temporal cortex, the other representing connectivity between the frontal/cingulate and angular/temporal cortices. Sociability affected 12 rs-fMRI traits when allowing for weakly correlated genetic instruments. Combing all three methods for gene prioritisation, we defined 17 highly prioritised genes, with DRD2 and LINGO1 showing the most robust evidence across all analyses. By integrating genetic and transcriptomics data, our gene prioritisation strategy may serve as a blueprint for future studies. The prioritised genes could be explored as potential biomarkers for social dysfunction in the context of neuropsychiatric disorders and as drug target genes.

9.
Psychol Med ; : 1-10, 2024 May 27.
Artigo em Inglês | MEDLINE | ID: mdl-38801094

RESUMO

BACKGROUND: Psychiatric disorders and type 2 diabetes mellitus (T2DM) are heritable, polygenic, and often comorbid conditions, yet knowledge about their potential shared familial risk is lacking. We used family designs and T2DM polygenic risk score (T2DM-PRS) to investigate the genetic associations between psychiatric disorders and T2DM. METHODS: We linked 659 906 individuals born in Denmark 1990-2000 to their parents, grandparents, and aunts/uncles using population-based registers. We compared rates of T2DM in relatives of children with and without a diagnosis of any or one of 11 specific psychiatric disorders, including neuropsychiatric and neurodevelopmental disorders, using Cox regression. In a genotyped sample (iPSYCH2015) of individuals born 1981-2008 (n = 134 403), we used logistic regression to estimate associations between a T2DM-PRS and these psychiatric disorders. RESULTS: Among 5 235 300 relative pairs, relatives of individuals with a psychiatric disorder had an increased risk for T2DM with stronger associations for closer relatives (parents:hazard ratio = 1.38, 95% confidence interval 1.35-1.42; grandparents: 1.14, 1.13-1.15; and aunts/uncles: 1.19, 1.16-1.22). In the genetic sample, one standard deviation increase in T2DM-PRS was associated with an increased risk for any psychiatric disorder (odds ratio = 1.11, 1.08-1.14). Both familial T2DM and T2DM-PRS were significantly associated with seven of 11 psychiatric disorders, most strongly with attention-deficit/hyperactivity disorder and conduct disorder, and inversely with anorexia nervosa. CONCLUSIONS: Our findings of familial co-aggregation and higher T2DM polygenic liability associated with psychiatric disorders point toward shared familial risk. This suggests that part of the comorbidity is explained by shared familial risks. The underlying mechanisms still remain largely unknown and the contributions of genetics and environment need further investigation.

10.
Cell Rep Med ; 5(5): 101529, 2024 May 21.
Artigo em Inglês | MEDLINE | ID: mdl-38703765

RESUMO

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.


Assuntos
Estudo de Associação Genômica Ampla , Cabeça , Neoplasias , Humanos , Cabeça/anatomia & histologia , Neoplasias/genética , Neoplasias/patologia , Feminino , Masculino , Polimorfismo de Nucleotídeo Único/genética , Variação Genética , Tamanho do Órgão/genética , Transdução de Sinais/genética , Adulto , Predisposição Genética para Doença
11.
medRxiv ; 2024 Mar 08.
Artigo em Inglês | MEDLINE | ID: mdl-38496672

RESUMO

The co-occurrence of insulin resistance (IR)-related metabolic conditions with neuropsychiatric disorders is a complex public health challenge. Evidence of the genetic links between these phenotypes is emerging, but little is currently known about the genomic regions and biological functions that are involved. To address this, we performed Local Analysis of [co]Variant Association (LAVA) using large-scale (N=9,725-933,970) genome-wide association studies (GWASs) results for three IR-related conditions (type 2 diabetes mellitus, obesity, and metabolic syndrome) and nine neuropsychiatric disorders. Subsequently, positional and expression quantitative trait locus (eQTL)-based gene mapping and downstream functional genomic analyses were performed on the significant loci. Patterns of negative and positive local genetic correlations (|rg|=0.21-1, pFDR<0.05) were identified at 109 unique genomic regions across all phenotype pairs. Local correlations emerged even in the absence of global genetic correlations between IR-related conditions and Alzheimer's disease, bipolar disorder, and Tourette's syndrome. Genes mapped to the correlated regions showed enrichment in biological pathways integral to immune-inflammatory function, vesicle trafficking, insulin signalling, oxygen transport, and lipid metabolism. Colocalisation analyses further prioritised 10 genetically correlated regions for likely harbouring shared causal variants, displaying high deleterious or regulatory potential. These variants were found within or in close proximity to genes, such as SLC39A8 and HLA-DRB1, that can be targeted by supplements and already known drugs, including omega-3/6 fatty acids, immunomodulatory, antihypertensive, and cholesterol-lowering drugs. Overall, our findings underscore the complex genetic landscape of IR-neuropsychiatric multimorbidity, advocating for an integrated disease model and offering novel insights for research and treatment strategies in this domain.

12.
Lancet Digit Health ; 6(3): e211-e221, 2024 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-38395541

RESUMO

The value of normative models in research and clinical practice relies on their robustness and a systematic comparison of different modelling algorithms and parameters; however, this has not been done to date. We aimed to identify the optimal approach for normative modelling of brain morphometric data through systematic empirical benchmarking, by quantifying the accuracy of different algorithms and identifying parameters that optimised model performance. We developed this framework with regional morphometric data from 37 407 healthy individuals (53% female and 47% male; aged 3-90 years) from 87 datasets from Europe, Australia, the USA, South Africa, and east Asia following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The multivariate fractional polynomial regression (MFPR) emerged as the preferred algorithm, optimised with non-linear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3000 study participants. This model can inform about the biological and behavioural implications of deviations from typical age-related neuroanatomical changes and support future study designs. The model and scripts described here are freely available through CentileBrain.


Assuntos
Benchmarking , Longevidade , Humanos , Masculino , Feminino , Encéfalo/diagnóstico por imagem , Modelos Estatísticos , Algoritmos
13.
Artigo em Inglês | MEDLINE | ID: mdl-38329535

RESUMO

Disruptive behavior disorders [including conduct disorder (CD) and oppositional defiant disorder (ODD)] are common childhood and adolescent psychiatric conditions often linked to altered arousal. The recommended first-line treatment is multi-modal therapy and includes psychosocial and behavioral interventions. Their modest effect sizes along with clinically and biologically heterogeneous phenotypes emphasize the need for innovative personalized treatment targeting impaired functions such as arousal dysregulation. A total of 37 children aged 8-14 years diagnosed with ODD/CD were randomized to 20 sessions of individualized arousal biofeedback using skin conductance levels (SCL-BF) or active treatment as usual (TAU) including psychoeducation and cognitive-behavioral elements. The primary outcome was the change in parents´ ratings of aggressive behavior measured by the Modified Overt Aggression Scale. Secondary outcome measures were subscales from the Child Behavior Checklist, the Inventory of Callous-Unemotional traits, and the Reactive-Proactive Aggression Questionnaire. The SCL-BF treatment was neither superior nor inferior to the active TAU. Both groups showed reduced aggression after treatment with small effects for the primary outcome and large effects for some secondary outcomes. Importantly, successful learning of SCL self-regulation was related to reduced aggression at post-assessment. Individualized SCL-BF was not inferior to active TAU for any treatment outcome with improvements in aggression. Further, participants were on average able to self-regulate their SCL, and those who best learned self-regulation showed the highest clinical improvement, pointing to specificity of SCL-BF regulation for improving aggression. Further studies with larger samples and improved methods, for example by developing BF for mobile use in ecologically more valid settings are warranted.

14.
Am J Med Genet B Neuropsychiatr Genet ; 195(1): e32951, 2024 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-37334623

RESUMO

The dense co-occurrence of psychiatric disorders questions the categorical classification tradition and motivates efforts to establish dimensional constructs with neurobiological foundations that transcend diagnostic boundaries. In this study, we examined the genetic liability for eight major psychiatric disorder phenotypes under both a disorder-specific and a transdiagnostic framework. The study sample (n = 513) was deeply phenotyped, consisting of 452 patients from tertiary care with mood disorders, anxiety disorders (ANX), attention-deficit/hyperactivity disorder (ADHD), autism spectrum disorders, and/or substance use disorders (SUD) and 61 unaffected comparison individuals. We computed subject-specific polygenic risk score (PRS) profiles and assessed their associations with psychiatric diagnoses, comorbidity status, as well as cross-disorder behavioral dimensions derived from a rich battery of psychopathology assessments. High PRSs for depression were unselectively associated with the diagnosis of SUD, ADHD, ANX, and mood disorders (p < 1e-4). In the dimensional approach, four distinct functional domains were uncovered, namely the negative valence, social, cognitive, and regulatory systems, closely matching the major functional domains proposed by the Research Domain Criteria (RDoC) framework. Critically, the genetic predisposition for depression was selectively reflected in the functional aspect of negative valence systems (R2 = 0.041, p = 5e-4) but not others. This study adds evidence to the ongoing discussion about the misalignment between current psychiatric nosology and the underlying psychiatric genetic etiology and underscores the effectiveness of the dimensional approach in both the functional characterization of psychiatric patients and the delineation of the genetic liability for psychiatric disorders.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Psiquiatria , Transtornos Relacionados ao Uso de Substâncias , Humanos , Transtorno do Deficit de Atenção com Hiperatividade/diagnóstico , Transtorno do Deficit de Atenção com Hiperatividade/genética , Psicopatologia , Transtornos de Ansiedade , Herança Multifatorial/genética
15.
Eur Arch Psychiatry Clin Neurosci ; 274(1): 45-58, 2024 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-37378697

RESUMO

Impaired response inhibition is commonly present in individuals with attention-deficit/hyperactivity disorder (ADHD) and their unaffected relatives, suggesting impaired response inhibition as a candidate endophenotype in ADHD. Therefore, we explored whether behavioral and neural correlates of response inhibition are related to polygenic risk scores for ADHD (PRS-ADHD). We obtained functional magnetic resonance imaging of neural activity and behavioral measures during a stop-signal task in the NeuroIMAGE cohort, where inattention and hyperactivity-impulsivity symptoms were assessed with the Conners Parent Rating Scales. Our sample consisted of 178 ADHD cases, 103 unaffected siblings, and 173 controls (total N = 454; 8-29 years), for whom genome-wide genotyping was available. PRS-ADHD was constructed using the PRSice-2 software. We found PRS-ADHD to be associated with ADHD symptom severity, a slower and more variable response to Go-stimuli, and altered brain activation during response inhibition in several regions of the bilateral fronto-striatal network. Mean reaction time and intra-individual reaction time variability mediated the association of PRS-ADHD with ADHD symptoms (total, inattention, hyperactivity-impulsivity), and activity in the left temporal pole and anterior parahippocampal gyrus during failed inhibition mediated the relationship of PRS-ADHD with hyperactivity-impulsivity. Our findings indicate that PRS-ADHD are related to ADHD severity on a spectrum of clinical, sub-threshold, and normal levels; more importantly, we show a shared genetic etiology of ADHD and behavioral and neural correlates of response inhibition. Given the modest sample size of our study, future studies with higher power are warranted to explore mediation effects, suggesting that genetic liability to ADHD may adversely affect attention regulation on the behavioral level and point to a possible response inhibition-related mechanistic pathway from PRS-ADHD to hyperactivity-impulsivity.


Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Adolescente , Transtorno do Deficit de Atenção com Hiperatividade/etiologia , Transtorno do Deficit de Atenção com Hiperatividade/genética , Estudos de Casos e Controles , Encéfalo/diagnóstico por imagem , Atenção/fisiologia , Tempo de Reação/fisiologia , Imageamento por Ressonância Magnética
16.
Cell Rep ; 42(12): 113513, 2023 12 26.
Artigo em Inglês | MEDLINE | ID: mdl-38039134

RESUMO

The nuclear receptor liver receptor homolog-1 (LRH-1) has been shown to promote apoptosis resistance in various tissues and disease contexts; however, its role in liver cell death remains unexplored. Hepatocyte-specific deletion of LRH-1 causes mild steatosis and inflammation but unexpectedly shields female mice from tumor necrosis factor (TNF)-induced hepatocyte apoptosis and associated hepatitis. LRH-1-deficient hepatocytes show markedly attenuated estrogen receptor alpha and elevated nuclear factor κB (NF-κB) activity, while LRH-1 overexpression inhibits NF-κB activity. This inhibition relies on direct physical interaction of LRH-1's ligand-binding domain and the Rel homology domain of NF-κB subunit RelA. Mechanistically, increased transcription of anti-apoptotic NF-κB target genes and the proteasomal degradation of pro-apoptotic BCL-2 interacting mediator of cell death prevent mitochondrial apoptosis and ultimately protect mice from TNF-induced liver damage. Collectively, our study emphasizes LRH-1 as a critical, sex-dependent regulator of cell death and inflammation in the healthy and diseased liver.


Assuntos
NF-kappa B , Fator de Necrose Tumoral alfa , Feminino , Camundongos , Animais , NF-kappa B/metabolismo , Fator de Necrose Tumoral alfa/metabolismo , Apoptose , Fígado/metabolismo , Hepatócitos/metabolismo , Receptores Citoplasmáticos e Nucleares/genética , Receptores Citoplasmáticos e Nucleares/metabolismo , Inflamação/patologia
17.
bioRxiv ; 2023 Dec 02.
Artigo em Inglês | MEDLINE | ID: mdl-38076938

RESUMO

We present an empirically benchmarked framework for sex-specific normative modeling of brain morphometry that can inform about the biological and behavioral significance of deviations from typical age-related neuroanatomical changes and support future study designs. This framework was developed using regional morphometric data from 37,407 healthy individuals (53% female; aged 3-90 years) following a comparative evaluation of eight algorithms and multiple covariate combinations pertaining to image acquisition and quality, parcellation software versions, global neuroimaging measures, and longitudinal stability. The Multivariate Factorial Polynomial Regression (MFPR) emerged as the preferred algorithm optimized using nonlinear polynomials for age and linear effects of global measures as covariates. The MFPR models showed excellent accuracy across the lifespan and within distinct age-bins, and longitudinal stability over a 2-year period. The performance of all MFPR models plateaued at sample sizes exceeding 3,000 study participants. The model and scripts described here are freely available through CentileBrain (https://centilebrain.org/).

18.
Neuroimage Clin ; 40: 103542, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37988996

RESUMO

BACKGROUND: Disruptive behavior in children and adolescents can manifest as reactive aggression and proactive aggression and is modulated by callous-unemotional traits and other comorbidities. Neural correlates of these aggression dimensions or subtypes and comorbid symptoms remain largely unknown. This multi-center study investigated the relationship between resting state functional connectivity (rsFC) and aggression subtypes considering comorbidities. METHODS: The large sample of children and adolescents aged 8-18 years (n = 207; mean age = 13.30±2.60 years, 150 males) included 118 cases with disruptive behavior (80 with Oppositional Defiant Disorder and/or Conduct Disorder) and 89 controls. Attention-deficit/hyperactivity disorder (ADHD) and anxiety symptom scores were analyzed as covariates when assessing group differences and dimensional aggression effects on hypothesis-free global and local voxel-to-voxel whole-brain rsFC based on functional magnetic resonance imaging at 3 Tesla. RESULTS: Compared to controls, the cases demonstrated altered rsFC in frontal areas, when anxiety but not ADHD symptoms were controlled for. For cases, reactive and proactive aggression scores were related to global and local rsFC in the central gyrus and precuneus, regions linked to aggression-related impairments. Callous-unemotional trait severity was correlated with ICC in the inferior and middle temporal regions implicated in empathy, emotion, and reward processing. Most observed aggression subtype-specific patterns could only be identified when ADHD and anxiety were controlled for. CONCLUSIONS: This study clarifies that hypothesis-free brain connectivity measures can disentangle distinct though overlapping dimensions of aggression in youths. Moreover, our results highlight the importance of considering comorbid symptoms to detect aggression-related rsFC alterations in youths.


Assuntos
Transtorno da Conduta , Comportamento Problema , Masculino , Criança , Adolescente , Humanos , Transtorno da Conduta/diagnóstico por imagem , Agressão/psicologia , Emoções , Encéfalo/diagnóstico por imagem
19.
Stem Cell Reports ; 18(11): 2222-2239, 2023 11 14.
Artigo em Inglês | MEDLINE | ID: mdl-37863044

RESUMO

Mechanisms that underlie homeostatic plasticity have been extensively investigated at single-cell levels in animal models, but are less well understood at the network level. Here, we used microelectrode arrays to characterize neuronal networks following induction of homeostatic plasticity in human induced pluripotent stem cell (hiPSC)-derived glutamatergic neurons co-cultured with rat astrocytes. Chronic suppression of neuronal activity through tetrodotoxin (TTX) elicited a time-dependent network re-arrangement. Increased expression of AMPA receptors and the elongation of axon initial segments were associated with increased network excitability following TTX treatment. Transcriptomic profiling of TTX-treated neurons revealed up-regulated genes related to extracellular matrix organization, while down-regulated genes related to cell communication; also astrocytic gene expression was found altered. Overall, our study shows that hiPSC-derived neuronal networks provide a reliable in vitro platform to measure and characterize homeostatic plasticity at network and single-cell levels; this platform can be extended to investigate altered homeostatic plasticity in brain disorders.


Assuntos
Células-Tronco Pluripotentes Induzidas , Plasticidade Neuronal , Humanos , Ratos , Animais , Células Cultivadas , Plasticidade Neuronal/fisiologia , Neurônios/metabolismo , Técnicas de Cocultura , Tetrodotoxina/farmacologia
20.
Neurosci Biobehav Rev ; 153: 105360, 2023 10.
Artigo em Inglês | MEDLINE | ID: mdl-37573899

RESUMO

Abnormal gestational weight gain (GWG) has been increasing globally, up to 47% of all pregnancies. Multiple studies have focused on the association between GWG and adverse neurodevelopmental outcomes in the offspring, however with inconsistent results. We performed a systematic review and meta-analysis to evaluate associations between excessive or insufficient GWG and offspring's neurodevelopmental outcomes. Meta-analysis of these 23 studies using a random-effects model revealed associations between excessive GWG and neurodevelopmental disorders (ASD & ID & ADHD together: OR=1.12 [95% CI 1.06-1.19]), ASD (OR=1.18 [95% CI 1.08-1.29]), ADHD (OR=1.08 [95% CI 1.02-1.14]), ASD with ID (OR=1.15 [95% CI 1.01-1.32]), and ASD without ID (OR=1.12 [95% CI 1.06-1.19]). Insufficient GWG was associated with higher risk for ID (OR=1.14 [95% CI 1.03-1.26]). These results emphasize the significant impact, though of small effect size, of GWG across multiple neurodevelopmental disorders. It is important to note that these results do not establish causality. Other factors such as genetic factors, gene-environment interactions may confound the relationship between GWG and neurodevelopmental outcomes. To better understand the role of GWG in neurodevelopmental disorders, future studies should consider using genetically sensitive designs that can account for these potential confounders.


Assuntos
Ganho de Peso na Gestação , Transtornos do Neurodesenvolvimento , Gravidez , Feminino , Humanos , Aumento de Peso , Transtornos do Neurodesenvolvimento/epidemiologia , Transtornos do Neurodesenvolvimento/etiologia , Índice de Massa Corporal
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