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Background: Attention-Deficit/Hyperactivity Disorder (ADHD) is commonly treated with methylphenidate (MPH). Although highly effective, MPH treatment still has a relatively high non-response rate of around 30%, highlighting the need for a better understanding of treatment response. Radiomics of T1-weighted images and Diffusion Tensor Imaging (DTI) combined with machine learning approaches could offer a novel method for assessing MPH treatment response., Purpose: To evaluate the accuracy of both conventional and radiomics approaches in predicting treatment response based on baseline T1 and DTI data in stimulant-naive ADHD participants., Methods: We performed a secondary analysis of a randomized clinical trial (ePOD-MPH), involving 47 stimulant-naive ADHD participants (23 boys aged 11.4 ± 0.4 years, 24 men aged 28.1 ± 4.3 years) who underwent 16 weeks of treatment with MPH. Baseline T1-weighted and DTI MRI scans were acquired. Treatment response was assessed at 8 weeks (during treatment) and one week after cessation of 16-week treatment (post-treatment) using the Clinical Global Impressions - Improvement scale as our primary outcome. We compared prediction accuracy using a conventional model and a radiomics model. The conventional approach included the volume of bilateral caudate, putamen, pallidum, accumbens, and hippocampus, and for DTI the mean fractional anisotropy (FA) of the entire brain white matter, bilateral Anterior Thalamic Radiation (ATR), and the splenium of the corpus callosum, totaling 14 regional features. For the radiomics approach, 380 features (shape-based and first-order statistics) were extracted from these 14 regions. XGBoost models with nested cross-validation were used and constructed for the total cohort (n = 47), as well as children (n = 23) and adults (n = 24) separately. Exact binomial tests were employed to compare model performance., Results: For the conventional model, balanced accuracy (bAcc) in predicting treatment response during treatment was 63 % for the total cohort, 32 % for children, and 36 % for adults (Area Under the Receiver Operating Characteristic Curve (AUC-ROC): 0.69, 0.33, 0.41 respectively). Radiomics models demonstrated bAcc's of 68 %, 64 %, and 64 % during treatment (AUC-ROCs of 0.73, 0.62, 0.69 respectively). These predictions were better than chance for both conventional and radiomics models in the total cohort (p = 0.04, p = 0.003 respectively). The radiomics models outperformed the conventional models during treatment in children only (p = 0.02). At post-treatment, performance was markedly reduced., Conclusion: While conventional and radiomics models performed equally well in predicting clinical improvement across children and adults during treatment, radiomics features offered enhanced structural information beyond conventional region-based volume and FA averages in children. Prediction of symptom improvement one week after treatment cessation was poor, potentially due to the transient effects of stimulant treatment on symptom improvement., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: M. Chen is funded by the China Scholarship Council (CSC) from the Ministry of Education of P.R. China. M.W.A. Caan is a shareholder of Nico.lab International Ltd. H.A. Marquering is a co-founder and shareholder of Nico.lab International Ltd., TrianecT, and inSteps. The other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Stimulant medication is effective in alleviating overall symptom severity of attention-deficit/hyperactivity disorder (ADHD), yet interindividual variability in treatment response and tolerability still exists. While network analysis has identified differences in ADHD symptom relations, the impact of stimulant medication remains unexplored. Increased understanding of this association could provide valuable insights for optimizing treatment approaches for individuals with ADHD. In this study, we compared and characterized ADHD symptom networks (including 18 ADHD symptoms) between stimulant-treated (n = 348) and untreated (n = 70) individuals with ADHD and non-ADHD controls (NACs; n = 444). Moreover, we compared symptom networks between subgroups defined by their stimulant treatment trajectory (early-and-intense use, late-and-moderate use). Stimulant-treated individuals with ADHD showed stronger associations between symptoms, compared with untreated individuals with ADHD and NACs. We found no differences in symptom networks between the stimulant treatment trajectory subgroups. Prospective longitudinal studies are needed to disentangle whether the identified differences stem from treatment or pre-existing factors., Competing Interests: Declarations Ethical approval This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the medical ethical committees of the VU University Medical Centre and Radboud University Medical Centre (NL23894.091.08). Informed consent We obtained written informed consent from all participants aged 12 years and older, and from parents for participants under 18, for participation in the NeuroIMAGE study and use of their de-identified data in analysis and publications. Competing interests JB has been in the past 3 years a consultant to / member of advisory board of / and/or speaker for Takeda, Medice, Angelini, Boehringer-Ingelheim, and Servier. He is not an employee of any of these companies, and not a stock shareholder of any of these companies. He has no other financial or material support, including expert testimony, patents, and royalties. All other authors have no competing interest or industry support to report., (© 2024. The Author(s).)

Background: Stimulant medication is commonly prescribed as treatment for attention-deficit/hyperactivity disorder (ADHD). While we previously found that short-term stimulant-treatment influences apparent cortical thickness development in an age-dependent manner, it remains unknown whether these effects persist throughout development into adulthood., Purpose: Investigate the long-term age-dependent effects of stimulant medication use on apparent cortical thickness development in adolescents and adults previously diagnosed with ADHD., Methods: This prospective study included the baseline and 4-year follow-up assessment of the "effects of Psychotropic drugs On the Developing brain-MPH" ("ePOD-MPH") project, conducted between June-1-2011 and December-28-2019. The analyses were pre-registered (https://doi.org/10.17605/OSF.IO/32BHF). T1-weighted MR scans were obtained from male adolescents and adults, and cortical thickness was estimated for predefined regions of interest (ROIs) using Freesurfer. We determined medication use and assessed symptoms of ADHD, anxiety, and depression at both time points. Linear mixed models were constructed to assess main effects and interactions of stimulant medication use, time, and age group on regional apparent cortical thickness., Results: A total of 32 male adolescents (aged mean ± SD, 11.2 ± 0.9 years at baseline) and 24 men (aged mean ± SD, 29.9 ± 5.0 years at baseline) were included that previously participated in the ePOD-MPH project. We found no evidence for long-term effects of stimulant medication use on ROI apparent cortical thickness. As expected, we did find age-by-time interaction effects in all ROIs (left prefrontal ROI: P=.002, right medial and posterior ROIs: P<.001), reflecting reductions in apparent cortical thickness in adolescents. Additionally, ADHD symptom severity (adolescents: P<.001, adults: P=.001) and anxiety symptoms (adolescents: P=0.03) were reduced, and more improvement of ADHD symptoms was associated with higher medication use in adults (P=0.001)., Conclusion: We found no evidence for long-term effects of stimulant-treatment for ADHD on apparent cortical thickness development in adolescents and adults. The identified age-dependent differences in apparent cortical thickness development are consistent with existing literature on typical cortical development., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 van der Pal, Walhovd, Amlien, Guichelaar, Kaiser, Bottelier, Geurts, Reneman and Schrantee.)

Duchenne muscular dystrophy (DMD) is caused by mutations in the DMD gene leading to the presence of premature termination codons (PTC). Previous transcriptional studies have shown reduced DMD transcript levels in DMD patient and animal model muscles when PTC are present. Nonsense-mediated decay (NMD) has been suggested to be responsible for the observed reduction, but there is no experimental evidence supporting this claim. In this study, we aimed to investigate the mechanism responsible for the drop in DMD expression levels in the presence of PTC. We observed that the inhibition of NMD does not normalize DMD gene expression in DMD. Additionally, in situ hybridization showed that DMD messenger RNA primarily localizes in the nuclear compartment, confirming that a cytoplasmic mechanism like NMD indeed cannot be responsible for the observed reduction. Sequencing of nascent RNA to explore DMD transcription dynamics revealed a lower rate of DMD transcription in patient-derived myotubes compared to healthy controls, suggesting a transcriptional mechanism involved in reduced DMD transcript levels. Chromatin immunoprecipitation in muscle showed increased levels of the repressive histone mark H3K9me3 in mdx mice compared to wild-type mice, indicating a chromatin conformation less prone to transcription in mdx mice. In line with this finding, treatment with the histone deacetylase inhibitor givinostat caused a significant increase in DMD transcript expression in mdx mice. Overall, our findings show that transcription dynamics across the DMD locus are affected by the presence of PTC, hinting at a possible epigenetic mechanism responsible for this process., Competing Interests: The authors declare no competing interest.