Striatal dopamine, functional connectivity, and salience processing in health and disease

Student thesis: Doctoral ThesisDoctor of Philosophy


The aim of the current work was twofold. First, to develop methods that allow for the useful integration of distinct methods of examining the human brain, namely positron emission tomography and functional magnetic resonance imaging. Second, to apply these methods to better understand the neurobiological mechanisms underlying the pathways between environmental exposures, schizophrenia, and psychotic symptoms. 
The introductory chapter provides an overview of the schizophrenia concept, the neurobiological systems under examination, and the methodologies used. Chapter 2 is a review article that discusses recent developments in our understanding of striatal structure and function, and specifically how striatal dysfunction may underlie many of the symptoms observed in schizophrenia. A specific issue discussed in Chapter 2 is, where precisely does striatal dopamine dysfunction occur in schizophrenia? Chapter 3 attempts to answer this using a quantitative approach. A meta-analysis of all studies that have used positron emission tomography (PET) to measure striatal dopamine function in schizophrenia, shows that dopamine dysfunction displays marked spatial variability, and does not occur uniformly across the striatum. I find that dopamine dysfunction occurs predominantly in the associative striatum, refuting the hypothesis that dysfunction within the limbic striatum specifically underlies psychotic symptoms. 
Chapter 4 builds on the results of the meta-analysis and uses an integrative PETfMRI approach to ask whether spatial variability in striatal dopamine function shapes psychopathology in psychosis. I show that dopamine function within striatal regions functionally linked to cortical sensorimotor networks is associated with baseline motor symptoms, while negative and affective symptoms, are linked to dopamine function in striatal regions linked to default mode and cinguloopercular networks respectively. Chapter 5 again looks at the question of psychopathology, but here I study individuals who have been exposed to risk factors for psychosis, but who have not yet developed a psychiatric disorder. I show that exposure to environmental risk factors is associated with reduced adaptive and increased aberrant salience measures. I also find that these differences in behaviour are related to differences in corticostriatal connectivity. 
Finally, Chapter 6 uses PET and fMRI to answer an ongoing question regarding neurobiological mechanisms underlying salience processing. Specifically – what is the relationship between mesolimbic dopamine function and the cortical salience network? This is a question of interest because both neural systems share an overlapping role and have been implicated in psychotic disorders. I show that while striatal dopamine release capacity is associated with reduced salience network connectivity, striatal dopamine synthesis capacity is associated with greater connectivity within the salience network, and that this is particularly the case for ‘hub’ nodes playing a central role in information processing. 
In summary, I show that dopamine dysfunction in schizophrenia does not exist uniformly across the striatum, but is greatest in the associative striatum. The clinical relevance of this is demonstrated by the finding that psychotic symptoms relate to variation in the spatial profile of striatal dopamine dysfunction. In addition, I find that striatal connectivity is altered in individuals exposed to environmental risk factors. Finally, I show how systems known to be crucial to salience processing are linked. Together these findings advance our understanding of schizophrenia by suggesting mechanisms via which striatal and cortical function are linked, how risk factors are associated with neurobiological changes, and how neurobiological abnormalities may shape psychotic symptoms.
Date of Award1 Nov 2019
Original languageEnglish
Awarding Institution
  • King's College London
SupervisorOliver Howes (Supervisor), Philip McGuire (Supervisor) & Mitul Mehta (Supervisor)

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