Association of Dopamine with Reward, Neuroleptic Response and Risk Genes: Multimodal Neuroimaging Insights on the Neurobiology of Schizophrenia


The etiology of schizophrenia (SCZ) remains elusive, though dopaminergic and genetic influences have been established as contributing factors to the disease’s pathophysiology. Current treatments for SCZ are ineffective in treating some core aspects of the disease, such as the negative and cognitive symptoms, and development of improved therapies is hampered by an incomplete understanding of the associated neurobiology. Reward processing studies in schizophrenia may lend insight into the biology of negative symptoms, though interpretation of findings in existing literature is limited by confounding cognitive and performance-based components of instrumental reward tasks. To isolate reward-related deficits from these contributing processes and medication effects, I used fMRI to study passive reward anticipation — in conditions of low cognitive demand — in patients with SCZ spectrum disorders during both arms of a double-blinded, placebo-controlled, atypical antipsychotic-withdrawal protocol. Relative to healthy controls, patients exhibit a diminished ventral striatal response to reward anticipation. The reduction was associated with both reward probability and negative symptoms, and was not significantly altered by medication. I then used PET to evaluate the neurochemical associations of the neurophysiological response to reward anticipation, revealing a positive relationship between ventral striatal dopamine (DA) synthetic tone and local fMRI-evaluated sustained response in both drug-free patients and healthy controls. Furthermore, D2/3R availability in patients predicts changes in the VST neurophysiological response to reward anticipation following treatment, such that higher basal D2/3R availability corresponds with greater VST response during medicated versus drug-free conditions. Finally, I provide the first in vivo evidence for a relationship between the SCZ risk gene ZNF804A and DA function. Future studies may enable identification of the mechanism through which ZNF804A affects the DA system and, possibly, the risk for schizophrenia. Collectively, this thesis emphasizes the importance of elucidating the complex relationship of DA with multiple levels of neurobiology in schizophrenia for improving our understanding of this devastating disease.
Thesis (Ph. D.)--Brown University, 2017


Hegarty, Catherine Elizabeth, "Association of Dopamine with Reward, Neuroleptic Response and Risk Genes: Multimodal Neuroimaging Insights on the Neurobiology of Schizophrenia" (2017). Neuroscience Theses and Dissertations. Brown Digital Repository. Brown University Library.