Methylphenidate Treatment and the Developing Brain in Attention-Deficit/Hyperactivity Disorder

Methylphenidate has been used for over 50 years for the treatment of attention-deficit/hyperactivity disorder (ADHD). The potential for long term methylphenidate treatment to have a negative impact on the developing brain and on the cognitive motivational development of children with ADHD has been the subject of intense debate. As methylphenidate is being increasingly used over long periods it is important to know whether evidence exists to support this view. Unfortunately this is an area of research that has been neglected. On the one hand, there are clear benefits in treating ADHD, but the uncertainty of long term benefits and risks makes the treatment of ADHD an urgent public health matter. The purpose of our proposal is to provide answers to the important questions related to the effects of long term use of methylphenidate on the development of cognition and brain development, by using the infrastructure of a large ongoing clinical cohort study, the NeuroIMAGE project, an extensive database of 369 ADHD combined subtype families (369 probands and their 130 affected [61 combined subtype, 50 inattentive subtype, and 19 hyperactive-impulsive subtype] and 391 unaffected siblings) and 149 control families (280 healthy controls and their siblings). These 1170 subjects were 6-18 years when assessed at baseline. Controls and their first degree relatives had no formal or suspected ADHD diagnosis. Apart from extensive longitudinal data regarding cognition and brain development we have pharmacists’ records with regard to the life-time prescriptions of the patients. Main objectives of our proposal include (1): To investigate the structural brain correlates of long term methylphenidate treatment, including caudate and cortex volumes (anterior cingulate, the right motor strip, the left middle/inferior frontal gyrus, and the right parieto-occipital region) as measured in a cohort of children with ADHD with and without exposure to methylphenidate and healthy controls at two time points, six years apart. (2): To explore the functional brain correlates of long term methylphenidate treatment, including structural and functional connectivity. Treatment with methylphenidate affects the regulation of this dopamine. Here the question will be answered how methylphenidate treatment history influences brain functioning and connectivity in fronto-striatal brain regions; (3): To evaluate possible cognitive effects associated with methylphenidate treatment history including cognitive flexibility, motivation, sensitivity to reward; and (4) To explore long term effects of methylphenidate use on working memory and inhibition. We will also explore the role of potential moderators, including various genotypes (dopamine related haplotypes), age, sex, socioeconomic status, family functioning, co‐medication, and negative lifestyle factors in the relationship between methylphenidate treatment and long‐term effects on brain development. Moderators identify in whom and under which circumstances treatment has different effects. Mediators identify why and how effects occur. We will make optimal use of the fact that some children have stopped methylphenidate (despite persisting presence of ADHD) whilst others have continued methylphenidate for many years. We also have access to probands and siblings with ADHD who have never used methylphenidate. Finally, the presence of healthy controls makes longitudinal comparison with normal development feasible. Thus, the NeuroImage ADHD cohort contains good numbers of methylphenidate naive children, of children with ADHD who have continued the use of methylphenidate till wave 2 as well as those who have discontinued methylphenidate between wave 1 and wave 2. The proposal is a naturalistic study. Confounding by indication is the main challenge to validity. Propensity score analysis will be applied to deal with possible indication bias, thus maximizing confounder balance between the groups. Collection of all longitudinal imaging and pharmacy data will be finished end 2011. Thus, all required data will be available upon the start of the proposed project. However, we have currently no financial means to process and code the lifetime pharmacists prescription records to conduct statistical analyses and draft scientific publication on the relationship between life time methylphenidate exposure and structural and functional brain development plus cognition. Therefore, we ask for funding for a full time PhD student for 48 months.