Dopamine D2-receptor Mapping in Restless Legs Syndrome and Human Behaviour

Molecular imaging techniques such as positron emission tomography (PET) allow for examination of biochemical markers directly in the living human brain. Such imaging studies have over the recent years provided important understanding of the functional role of dopaminergic neurotransmission in motor and higher-order brain functions. The first aim of the present thesis was to examine the dopamine (DA) system in Restless Legs Syndrome (RLS). The second aim was to extend current knowledge on the physiological role of DA neurotransmission, including involvement in components of complex human behaviour. Sixteen patients with RLS and sixteen matched control subjects were examined with PET. Using the radioligands [C]raclopride for striatum and [C]FLB 457 for extra-striatal regions in a total of 96 PET examinations, a detailed mapping of D2receptor distribution was performed employing both region-of-interest and voxel-based methods. In study II-V, only control subjects were included in the analysis. In the first study, D2-receptor binding in RLS patients and control subjects was compared. Patients showed higher receptor availability in both striatal and extra-striatal brain regions. Increased D2 binding may correspond to higher receptor densities or lower levels of endogenous DA, and the results are thus consistent with a hypoactive DA system in RLS since low DA levels can lead to receptor upregulation. In a subsequent study, diurnal effects on D2-receptor availability was examined by comparing PET examinations performed AM and PM. Individuals in the lower age range showed reduced PM binding while in older subjects binding increased, an effect which was statistically significant in limbic and cortical brain regions. The results imply a diminished DA release in the evening with increasing age. In the third study, striatal D2-receptor binding was examined in relation to cognitive performance. Receptor availability in limbic striatum was related to performance in tests of episodic memory. By contrast, D2 binding in associative and sensorimotor striatum showed associations to the non-episodic tasks verbal fluency and general knowledge. These findings provide the first biochemical evidence in man for a functional subdivision of the striatum. In study four, interregional correlations and individual patterns in D2-receptor availability was examined. Significant correlations were found between binding in several brain regions, but not all. Specifically, the results do not support the use of striatal DA markers as an index of global DA function. Furthermore, it was demonstrated that individual binding profiles could be reliably categorized using dimension reduction and clustering approaches. In the final study, D2-receptor binding was examined in relation to a measure of the personality trait social desirability. A negative relationship was shown for hippocampus-amygdala, whereas a trend-level correlation in the same direction was found for the striatum. The results add to recent evidence in support of a role for the DA system in socially desirable behaviour, and extend this research into brain regions of relevance for emotional processing and learning. In summary, the present work provides new knowledge on the functional roles of the DA system in RLS and human behaviour, and supports the rationale of performing an anatomically detailed mapping of DA markers in clinical PET studies. To Iris, Jakob and Bruno LIST OF PUBLICATIONS I. Cervenka S, Palhagen SE, Comley RA, Panagiotidis G, Cselenyi Z, Matthews JC, Lai RY, Halldin C, Farde L (2006) Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain 129:2017-2028. II. Cervenka S, Halldin C, Farde L (2008) Age-related diurnal effect on D2 receptor binding: a preliminary PET study. Int J Neuropsychopharmacol:1-8. III. Cervenka S, Backman L, Cselenyi Z, Halldin C, Farde L (2008) Associations between dopamine D2-receptor binding and cognitive performance indicate functional compartmentalization of the human striatum. Neuroimage 40:1287-1295 IV. Cervenka S, Fransen E, Varrone A, Halldin C, Farde L Regional analysis of D2-receptor binding in striatal and extrastriatal brain regions: correlations and individual patterns. Submitted V. Cervenka S, Halldin C, Farde L Association between D2-receptor binding in the mesolimbic dopamine system and social desirability. Submitted.