Age-dependent effects of cumulative methylphenidate exposure on brain structure and symptom amelioration in youth with ADHD: A longitudinal MRI study

Abstract

Methylphenidate is known to alleviate attention-deficit/hyperactivity disorder (ADHD) symptoms. However, methylphenidate's age-dependent effects on brain structure have not been well studied. This longitudinal MRI study investigated the effect of cumulative methylphenidate exposure on brain structure and ADHD-related symptoms. Eighty-nine individuals with DSM-5 ADHD and 91 typically developing controls (TDC) were assessed with MRI for brain structure and the parent-rated SNAP-IV questionnaire for ADHD-related symptoms at baseline and follow-up. The average follow-up interval was 4.86 years. Participants were divided into two age-based groups at a baseline age cutoff of 12 years. In the early-exposure subgroup (baseline age < 12 years), distinct developmental differences were noted between the ADHD and TDC groups in various frontal regions. Increased cumulative methylphenidate dosage was associated with increased gray matter volumes in several frontal areas, such as the right paracentral, caudal middle frontal, superior frontal, lateral orbitofrontal, rostral middle frontal, precentral cortices, left pars opercularis, paracentral, and superior frontal cortices in the early-exposure subgroup. Additionally, greater volumetric increases in specific frontal regions, including the right rostral middle frontal, right paracentral, right superior frontal, and left paracentral cortices, correlated with more significant improvements in oppositional symptoms. Conversely, the late-exposure subgroup (baseline age > 12 years) showed no significant differences in cortical development or associations between methylphenidate and brain structure. Our findings indicate that early methylphenidate exposure may affect frontal brain morphology and its association with symptom improvement in ADHD. These age-dependent patterns of psychostimulants on brain structure provide further insight into treatment response and disorder progression monitoring.