Neurodevelopmental effects of omega-3 fatty acids and its combination with Methylphenidate in iPSC models of ADHD

Attention-Deficit/Hyperactivity Disorder (ADHD) has been linked to altered neurodevelopmental processes, including proliferation and differentiation of neural stem cells (NSC). We aimed to investigate the role of Wnt signaling, a pathway critical for brain development, in ADHD and to determine if modulation of this pathway using ω-3/6 polyunsaturated fatty acids (PUFAs) may provide a beneficial treatment approach. Given the symptom heterogeneity in ADHD and the limited response to conventional therapies for some patients, we examined the effects of ω-3/6 PUFA treatment combined with Methylphenidate (MPH) on neurodevelopmental mechanisms using induced pluripotent stem cell (iPSC)-derived NSCs, comparing controls to ADHD patients. Our results show that ω-3/6 PUFAs differentially regulate Wnt activity in NSCs depending on the patient's condition and the composition of the treatments. These findings highlight the potential of ω-3 PUFA treatment as personalized support for neurodevelopmental processes in ADHD. They also emphasize the importance of investigating ADHD subgroups, including those unresponsive to stimulant treatments, as they may exhibit distinct phenotypes.