Time for action: assessment of neural variability in the treatment of developmental disorders

Abstract

Developmental disorders such as autism spectrum disorder (ASD) and attention deficit hyperactivity disorder (ADHD) are extremely debilitating. Furthermore, their prevalence has risen exponentially over the last decades. Classified based on behavioral observations, according to the diagnostic statistical manual of mental disorders (DSM-5), these constructs are heterogeneous by clinical definition. In this thesis we studied samples of children with ASD with and without epilepsy, children with ADHD and a young woman with tuberous sclerosis complex. Our overall aim was to use neural measures to dissect the interindividual variability that characterizes developmental disorders in order to better predict treatment response. We used varying samples and research designs to achieve this aim. The measures included neuroimaging such as event related potentials (ERPs), functional magnetic resonance imaging (fMRI) and measures of cognition and behavior. Chapter 2 of this thesis shows that as a group, children with autism spectrum disorder show changes in auditory sensory processing, from early, preconscious to later, conscious levels of processing. Chapter 3 shows that children with ASD and comorbid epilepsy show enhanced frequency-based mismatch negativity compared to typically developing (TD) children and children with ASD without epilepsy, suggesting enhanced automatic discrimination. This contrast was not found for the whole ASD group, nor was a difference observed in behavioral measures. In addition, in chapter 4 we found that children with ADHD show inter-individual differences in methylphenidate response, with improvements in reactive stopping possibly more related to clinical (behavioral) MPH response. The last chapter (5) shows that the diuretic bumetanide was found to ameliorate behavioral problems associated with tuberous sclerosis complex in a case study of a young woman with TSC. Taken together, this thesis emphasizes the heterogeneity of developmental disorders, the importance of studying neural correlates and the need for bridging the gap between research and the clinic. The studies in this thesis provide evidence that studying neural variability in developmental disorders may indeed be useful for both pathophysiological understanding and the prediction and assessment of possible treatment targets.