Neurobiological heterogeneity in ADHD

Abstract

Attention-Deficit/Hyperactivity Disorder (ADHD) is a highly heterogeneous disorder clinically. Symptoms take many forms, from subtle but pervasive attention problems or dreaminess up to disruptive and unpredictable behavior. Interestingly, early neuroscientific work on ADHD assumed either a homogeneous neurobiological substrate or one that somehow mimicked clinical heterogeneity. Recent work however, has started to emphasize multiple neurobiological pathways towards ADHD, regardless of its clinical expression. The work in this thesis shows that the neurobiological profile of ADHD is as heterogeneous as its clinical presentation. Using a number of different approaches, including anatomical neuroimaging, neuropsychological testing, measures of the prenatal environment and a candidate gene approach, this thesis investigates multiple forms of heterogeneity. First, it investigates heterogeneity within a brain circuit known to be involved in the disorder: the frontostriatal system. A combination of diffusion tensor imaging (DTI) and magnetization transfer imaging (MTI) was used to investigate microstructural organization and myelination of the white matter tract between the striatum and the prefrontal cortex. Results showed that frontostriatal microstructural organization but not myelination was reduced in ADHD. Second, heterogeneity between children with ADHD was investigated, in terms of the cognitive impairments they present with. Results showed that a neurocognitive subtyping of ADHD is possible, based on the presence of deficits in either cognitive control, temporal processing or reward sensitivity. A second study in this section reports on differences in the neuroanatomical profile of ADHD across the intelligence scale. Two anatomical neuroimaging approaches were used: Volumetric analysis and cortical thickness. Results suggested that ADHD with lower IQ is more associated with a neuroanatomical developmental delay, whereas ADHD with higher IQ may be associated with widespread but subtle brain volume reductions that are developmentally stable. Two studies on etiological heterogeneity of the changes in cerebellum volume in ADHD constitute the final focus of this thesis. The first investigates the effects of prenatal exposure to alcohol and cigarette smoke on cerebellum volume. The results suggest that such exposure may be a factor in the cerebellum changes in ADHD, likely in concert with genetic effects. The final study considers both prenatal environment and a recently identified candidate gene for ADHD (XKR4). Here, it is shown that both affect cerebellum volume. Importantly, the true effects of the XKR4-gene on cerebellum volume were not evident until parental environment was also considered in the analyses. Together, these studies suggest that multiple neurobiological pathways with both genetic and environmental etiologies may play a role in ADHD. This thesis finally discusses how accepting neurobioloical heterogeneity in ADHD, a disorder deemed unitary by virtue of its classification, has significant implications for how we conceptualize ADHD from a neurobiological perspective. Dissecting the phenotype along neurobiologically informative dimensions will be an important step in reducing phenotypic complexity. Etiological research, genetic studies in particular, may have more power to detect relevant genetic variants when more neurobiologically homogeneous subgroups of patients are considered. The studies in this thesis suggest that such a neurobiological subtyping is possible. In addition, including environmental factors in neurobiological research is an important next step to take.