Attention-deficit/hyperactivity disorder : Alterations of motor behaviour and dopaminergic transmission

Abstract: Altered catecholaminergic neurotransmission in the brain has long been thought to be of importance in the regulation of motor behavior and cognitive performance in children who had symptoms of distractability, impulsivity and clumsiness. The dopamine theory of AD/HD has mainly been substantiated by: i) the effects of psychostimulants, which target the dopamine transporter (DAT), and thereby reduce impulsiveness and inattentiveness, increase the striatal cerebral blood flow and functional activity, and ii) the evidence from linkage studies associating the AD/HD syndrome with allelic variations of genes encoding the dopamine transporter and, possibly, the dopamine D4 receptors. However, the central regulatory mechanisms of dopamine neurotransmission in AD/HD have not been established yet. The main aim of this thesis was to examine the dopaminergic system in vivo in children with AD/HD by using positron emission tomography (PET). Twelve adolescents with AD/HD and ten young adults were investigated applying the double-tracer paradigm. Presynaptic and postsynaptic dopamine markers, DAT and dopamine D2 receptors, were mapped using the radioligands [11C]PE2I and [11C]raclopride. In the group of adolescents with ADHD, we also investigated relationship between the central dopamine markers and behavioral/cognitive performance. A new radioligand [11C]PE2I that has a high affinity and selectivity to the central DAT was used. Its favourable signal-to-background ratio enabled us to quantify the DAT density in the human striatum and midbrain; cross-validation of quatification methods of [11C]PE2I binding permitted its application in the clinical study. The PET measurements showed that the DAT and DRD2 density in the striatum did not differ between adolescents and young adults once a correction had been made for age. Thus, the initial findings of increased DAT in the striatum in AD/HD reported in the literature were not confirmed. The decreased regional density of DAT found in the substantia nigra/ventral tegmentum rather suggests a shift in the focus of the pathophysiology of AD/HD to the midbrain structures. In addition, positive correlations between hyperactivity levels and the density of dopamine markers in the striatum support similar reports by other authors and provide evidence for the involvement of the dopamine system in the pathophysiology of AD/HD. The AD/HD syndrome is a heterogenous diagnostic entity, and it is still a matter of debate whether perception and movement coordination problems are a constituent part of it. We investigated movement coordination problems from the perspective of motor control theories with a load lifting task, providing measurements of manipulative movements and associated postural adjustments. Fifty two children were investigated, including an additional control group of younger children, with the intention of addressing the developmental aspects of motor behavior. The results showed that children with AD/HD and developmental coordination disorder, or both, have a deficit in the programming of their motor behavior that is related to the severity/complexity of the syndrome, but which does not correspond to the motor performance of younger children. The deficient parametric control of the motor output, and lack of temporal coordination between the lifting movement and the postural responses limited the adaptation of the motor behavior to the environment.