Methylphenidate (MPH) is a common treatment for ADHD, but 20-30% of patients do not respond adequately. Animal studies have suggested that MPH may induce inflammation, potentially affecting its efficacy and tolerance, which could explain certain side effects and inadequate clinical responses in some individuals. However, the underlying mechanisms of ADHD-related brain inflammation and potential MPH-induced inflammation in humans have not been explored. Nutritional interventions, including the use of polyphenols, may potentially reduce inflammation associated with ADHD and MPH treatment. Further studies are needed to assess whether polyphenols can improve ADHD symptoms and the efficacy of MPH by reducing inflammation. The objectives of this project are as follows: i) Define nutritional and inflammatory profiles in children and adolescents with ADHD compared to age- and sex-matched typically developing peers; ii) Evaluate inflammatory profiles with and without MPH and their relationships with symptom severity, clinical tolerance, and treatment efficacy in children and adolescents with ADHD; iii) Analyze in detail associated pathophysiological mechanisms and potential therapeutic targets; iiii) Test the in vitro effects of anti-inflammatory and antioxidant agents such as polyphenols to identify candidates for future supplementary studies on MPH augmentation in humans. This project aims to discover anti-inflammatory pathways to alleviate ADHD symptoms and improve MPH tolerance, while providing insights into peripheral and cerebral immune profiles in ADHD patients.