Target Trial Emulation in ADHD

Background 

Attention-deficit/hyperactivity disorder affects around 5% of children and is characterized by symptoms of inattention, hyperactivity and impulsivity. Children with ADHD often experience trouble at school and home, and it has been shown that their behavioral symptomatology is often accompanied by cognitive deficits. Though estimates vary considerably, symptoms which cause substantial impairment in daily life will subside in adulthood in only about half of children diagnosed with ADHD or less. Stimulant medication has proven effective in reducing symptoms in children, and has been postulated to be a factor for observed remission in adulthood.

Brain imaging in ADHD

Advances in brain imaging assessments have demonstrated that ADHD is accompanied by a number of neurobiological features, including differences in brain morphology such as volume and cortical thickness. For instance, seminal work in the field has demonstrated that children with ADHD diagnoses show a delay in cortical development over time. Further, when tracked into adulthood, children who continue to suffer from symptoms show structural and functional brain features which are distinct from those who remit. Little work has explored neurodevelopment in the context of stimulant medication use and whether any associated brain changes are related to long-term symptom reductions.

Making Causal Inferences

The ‘gold standard’ for determining such causal relationships between treatment-induced brain changes and an accompanying relief from symptomatology is the randomized controlled trial (RCT). However, RCTs which utilize neuroimaging are expensive and are as a result often relatively small scale and limited in scope. Given these hurdles, limited information is available on the effects of ADHD medication on brain development. Further, in some cases trials are impossible due to ethical reasons, for example, ascertaining the effect of treatment of ADHD with stimulant medication.

Target Trial Emulation

This work aims to expand our present understanding of the neurodevelopmental trajectories of children with ADHD symptoms. Specifically we will explore to what extent medication for ADHD affects how the brain develops, and to what extent those changes are accompanied by symptom reductions. Further, the scope of our ability to make causal inferences in the absence of randomized trials has traditionally been limited, however recent methodological developments allow for randomized trials to be ‘emulated’ using sophisticated epidemiological techniques (Target Trial Emulation, TTE).

In this study, we will utilize the world’s largest single-site longitudinal study of brain development in children to assess the structural and functional neurodevelopmental trajectories of dimensional ADHD symptoms in the general population. We will also utilize TTE to design our observational study as though it were a randomized trial of the effect of ADHD medication on brain development, and determine whether these observe brain changes are related to symptom changes over time.

Vrienden van Sophia Foundation

Internal collaborations

• Department of Child and Adolescent Psychiatry/Psychology
• Department of Epidemiology

• Ryan Muetzel
• Jeremy Labrecque 
• Henning Tiemeier
• Annet Dijkzeul