Brain age and epigenetic clocks in offspring at high familial risk for schizophrenia and bipolar disorder

Objective: Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurodevelopmental disorder that is commonly treated with stimulants like methylphenidate. In addition to attentional, hyperactive and impulsive symptoms, cognitive functions like response inhibition are commonly affected in ADHD. Methylphenidate effectively alleviates these symptoms by inhibiting the dopamine and noradrenaline transporters (DAT/NET) in the brain, leading to increased extracellular dopamine and noradrenaline levels. However, the role of specific dopamine and noradrenaline receptor subtypes in methylphenidate's effects on brain function and cognition remains unclear. This study addressed this gap by examining their contribution to resting-state functional connectivity (FC), and its relation to response inhibition. Furthermore, we evaluated the agedependency of these effects, as previous research suggests methylphenidate's effects may differ in children and adults[1]. Methods: We included 50 boys (aged 10-12 years) and 49 men (aged 23-40 years) with ADHD as part of the ePOD-Methylphenidate project[2]. All participants were stimulant treatment-naive. Participants performed a response inhibition task and underwent 3T MRI (anatomical and resting-state functional MRI) before and 90 minutes after a single-dose methylphenidate-challenge (0.5 mg/kg; max. 20mg in children, max. 40 mg in adults). Resting-state functional MR data was processed using fMRIPrep and ICA-AROMA. Mean framewise displacement (FD) was extracted and dprime was calculated as a measure of response inhibition task performance[3]. We applied REACT[4] to evaluate FC weighted for DAT, NET, D1-receptor and D2/3-receptor distributions (i.e. receptor-enriched FC). Using FSL randomise (v6.0.7; 5000 iterations, tfce, FWEcorrection) we identified (methylphenidate-induced changes in) significant receptor-enriched FC (one-sample t-tests, P-threshold