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Both genetic (polygenicity) and environmental variables interplay in the etiology of this disorder. The Wnt signaling pathway, which regulates proliferation and differentiation during neurodevelopment, has been implicated in ADHD. Clinically, individuals with ADHD may exhibit delays in structural and functional brain development. Available evidence suggests that methylphenidate (MPH) treatment can potentially improve these delays. However, the molecular and cellular mechanisms underlying ADHD and the therapeutic targets of MPH are not yet completely elucidated. In a pilot investigation, the proliferation of neural stem cells (NSCs) derived from induced pluripotent stem cells (iPSCs) was significantly lowered in ADHD male patients. Yet, we did not observe any variations in proliferation rates during the iPSC stage. To extend the earlier results, we increased the sample size to include females, explored whether MPH may improve NSC proliferation in ADHD and clarified the role of the Wnt pathway. To do so, iPSC and NSC proliferation from five ADHD patients and five controls was assessed. The results corroborated our previous findings of decreased proliferation in ADHD NSCs. Conversely, ADHD NSC proliferation was modestly regulated by MPH treatment at 10\u00a0nM, which also showed modulatory effects on Wnt signaling in this group. Interestingly, no increase in proliferation was seen when DKK1 blocked Wnt signaling before MPH treatment. These findings suggest MPH regulates the canonical Wnt pathway and may partially explain ADHD-related neurodevelopmental abnormalities and MPH-specific benefits.<\/jats:p>","DOI":"10.1007\/s00702-025-02988-y","type":"journal-article","created":{"date-parts":[[2025,7,28]],"date-time":"2025-07-28T05:29:47Z","timestamp":1753680587000},"page":"169-188","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Assessing the effects of methylphenidate in proliferation and Wnt activity of neuronal stem cells from attention deficit\/hyperactivity disorder patients"],"prefix":"10.1007","volume":"133","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7414-2250","authenticated-orcid":false,"given":"Cristine Marie","family":"Yde Ohki","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Natalie Monet","family":"Walter","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7428-7644","authenticated-orcid":false,"given":"Lukasz","family":"Smigielski","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Audrey","family":"Bender","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Michelle","family":"Rickli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8161-8683","authenticated-orcid":false,"given":"Susanne","family":"Walitza","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8505-7265","authenticated-orcid":false,"given":"Edna","family":"Gr\u00fcnblatt","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"2988_CR1","first-page":"371","volume":"7","author":"TM Achenbach","year":"1991","unstructured":"Achenbach TM, Edelbrock C (1991) Child behavior checklist. 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E.G. received research grant support from MEDICE Arzneimittel P\u00fctter GmbH & Co. KG. S.W. has received royalties in the last 5\u00a0years from Thieme, Hogrefe, Kohlhammer, Springer, Beltz. In 2023, she received honoraria as a speaker from Takeda. Her work has been supported in the last years by the Swiss National Science Foundation (SNF), different EU FP7s programs, HSM (Hochspezialisierte Medizin) of the Canton of Zurich, BfArM Germany, ZInEP, Hartmann M\u00fcller Stiftung, Olga Mayenfisch Stiftung, Gertrud Thalmann Stiftung, Vontobel, Unicentia, Erika Schwarz Stiftung, Heuberg Fonds, National Government of Health (BAG), Gesundheitsf\u00f6rderung Schweiz and Horizon Europe. Outside professional activities and interests are declared under the link of the University of Zurich\n                      \n                      .","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Conflict of interest"}}]}}