Correlation of altered intrinsic functional connectivity with emotion dysregulation in ADHD Youths
Notice bibliographique
Résumé
Background: Attention-deficit hyperactivity disorder (ADHD) is one of the most common psychiatric disorders in children and adolescents affecting over 5% of the population worldwide.Methylphenidate (MPH), the first line treatment for this multifactorial neurodevelopmental disorder, seems to ameliorate brain maturational delays in ADHD patients [1].However, molecular mechanisms involved in this process remains elusive.Genetic studies indicate a possible involvement of the Wnt signaling in ADHD [2], given that this pathway plays a fundamental role in neurodevelopment, orchestrating important cellular processes, such as proliferation, differentiation, and maturation [3].Objectives: This study aims to test the hypothesis that MPH is implicated with Wnt signaling activation in patients, which might ameliorate impaired neurodevelopment observed in the clinical setting.Methods: ADHD patients responding to MPH treatment and neurotypical controls (6-18 years old) were recruited by the Department of Child and Adolescent Psychiatry and Psychotherapy, University of Zurich.Peripheral Blood Mononuclear Cells (PBMCs) or plucked hair-derived keratinocytes from probands will be reprogrammed via Sendai virus transduction to generate iPSCs [4,5].Subsequently, NSCs will be derived, as well as forebrain cortical neurons (FCNs).Wnt reporter assays will be performed in NSCs to analyze Wnt activation after treatment with Wnt-agonists, the antagonist DKK1, and MPH, assessing EC50/IC50 to further compare ADHD and control groups.To check possible differences in proliferation, growth rates of iPSCs and NSCs will be measured in xCELLigence/Wst-1 assays.Functionally, FCNs will be tested regarding synaptogenesis in ADHD and controls via immunocytochemistry, while transcriptomics and protein expression of key Wnt-related genes and proteins will be assessed in these three developmental stages, by qPCR/single-cell RNA sequencing and Western Blot, respectively.ADHD and control groups will be compared before and after MPH treatment.Preliminary Results: In growth rate analysis, we verified that there were no significant differences between ADHD iPSCs and controls, by both xCELLigence and Wst-1 assay (Mann Whitney, n.s.; 2 and 3 independent experiments, respectively).However, there were differences when NSC proliferation was analyzed via xCELLigence (Mann Whitney, ***p¼0.0001; 2 independent experiments).Subsequently, the expression of key Wnt-related genes has been assessed in iPSCs and neurons.Transcriptomic expression of DKK1, an Wnt signaling inhibitor, tends to be increased in neurons belonging to individuals genetically predisposed to ADHD, in contrast to a negative correlation in iPSCs (Spearman correlation coefficient 0.691 at the 0.01 level and R2 ¼ 0.225; 2 independent experiments).Conclusion: Our preliminary results point out that expression of Wnt-related genes and proliferation might be dependent on genetic predisposition to ADHD and the neurodevelopmental stage.Additionally, NSCs seem to proliferate less in ADHD than controls, which might be associated with the brain maturational delays observed in patients.Overall, our findings will facilitate the understanding of the effects of MPH treatment in ADHD in cellular phenotypes and on Wnt activity in patient-specific neural cell models, broadening possibilities for new approaches, preventive measures, and therapeutic targets.References [1] Frodl, T. & Skokauskas, N. Meta-analysis of structural MRI studies in children and adults with attention deficit hyperactivity disorder indicates treatment effects.
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Comment cette classification a été obtenuedéplier
Prédiction machine sur la base complète
Imitation des enseignantsNi prévalence calibrée, ni vérité terrain. Validation humaine à venir. Le volet Gemma est une étiquette directe du modèle pour chaque travail de la base, lue sur la notice réduite au titre. Le volet Codex est un classifieur appris des 10 348 étiquettes directes de Codex et calibré sur les taux pondérés de l'échantillon; les champs sans appui suffisant ne portent aucun appel Codex. Le mode candidate est l'union des deux volets; le consensus est leur intersection. Ces sorties portent le statut machine_predicted_unvalidated et ne sont pas des étiquettes humaines.
Scores du classifieur distillé par catégorie (deux têtes)
| Catégorie | Codex | Gemma |
|---|---|---|
| Métarecherche | 0,000 | 0,001 |
| Méta-épidémiologie (sens strict) | 0,000 | 0,000 |
| Méta-épidémiologie (sens large) | 0,000 | 0,000 |
| Bibliométrie | 0,001 | 0,000 |
| Études des sciences et des technologies | 0,000 | 0,000 |
| Communication savante | 0,001 | 0,000 |
| Science ouverte | 0,000 | 0,000 |
| Intégrité de la recherche | 0,000 | 0,000 |
| Charge utile insuffisante (le modèle a refusé de juger) | 0,003 | 0,000 |
Scores machine (provisoires)
Les deux têtes enseignantes du modèle étudiant, lues sur ce travail. Un score ordonne la base pour la relecture; il n'affirme jamais une catégorie, et le statut de validation accompagne chaque rangée tel quel.
Scores de référence d'un modèle non mature (critères de maturité non atteints, 7 itérations). Un score ordonne; il n'affirme jamais une catégorie.
score_only:v0-immature-baseline · tel quel depuis la passe de notation : score_only signifie que le nombre peut ordonner les travaux, et qu'aucune étiquette de catégorie n'en découleClassification
machine, non validéePrédiction automatique; un appel candidat d’une seule source (Gemma direct ou Codex distillé), pas un consensus.
Le détail, modèle par modèle et score par score, se trouve en fin de page sous « Comment cette classification a été obtenue ».