Correlation of altered intrinsic functional connectivity with emotion dysregulation in ADHD Youths
Bibliographic record
Abstract
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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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.001 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.001 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.003 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".