京都大学 / 新制・論文博士 / 博士(医学) / 乙第13570号 / 論医博第2296号 / 新制||医||1069(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 花川 隆, 教授 渡邉 大, 教授 高橋 淳 / 学位規則第4条第2項該当 / Doctor of Medical Science / Kyoto University / DFAM

The aim of this thesis is to improve our understanding of the neural systems involved in schizophrenia by suggesting possible avenues for future computational modelling in an attempt to make sense of the vast number of studies relating to the symptoms and cognitive deficits relating to the disorder. This multidisciplinary research has covered three different levels of analysis: abnormalities in the microscopic brain structure, dopamine dysfunction at a neurochemical level, and interactions between cortical and subcortical brain areas, connected by cortico-basal ganglia circuit loops; and has culminated in the production of five models that provide useful clarification in this difficult field. My thesis comprises three major relevant modelling themes. Firstly, in Chapter 3 I looked at an existing neural network model addressing the Neurodevelopmental Hypothesis of Schizophrenia by Hoffman and McGlashan (1997). However, it soon became clear that such models were overly simplistic and brittle when it came to replication. While they focused on hallucinations and connectivity in the frontal lobes they ignored other symptoms and the evidence of reductions in volume of the temporal lobes in schizophrenia. No mention was made of the considerable evidence of dysfunction of the dopamine system and associated areas, such as the basal ganglia. This led to my second line of reasoning: dopamine dysfunction. Initially I helped create a novel model of dopamine neuron firing based on the Computational Substrate for Incentive Salience by McClure, Daw and Montague (2003), incorporating temporal difference (TD) reward prediction errors (Chapter 5). I adapted this model in Chapter 6 to address the ongoing debate as to whether or not dopamine encodes uncertainty in the delay period between presentation of a conditioned stimulus and receipt of a reward, as demonstrated by sustained activation seen in single dopamine neuron recordings (Fiorillo, Tobler & Schultz 2003). An answer to this question could result in a better understanding of the nature of dopamine signaling, with implications for the psychopathology of cognitive disorders, like schizophrenia, for which dopamine is commonly regarded as having a primary role. Computational modelling enabled me to suggest that while sustained activation is common in single trials, there is the possibility that it increases with increasing probability, in which case dopamine may not be encoding uncertainty in this manner. Importantly, these predictions can be tested and verified by experimental data. My third modelling theme arose as a result of the limitations to using TD alone to account for a reinforcement learning account of action control in the brain. In Chapter 8 I introduce a dual weighted artificial neural network, originally designed by Hinton and Plaut (1987) to address the problem of catastrophic forgetting in multilayer artificial neural networks. I suggest an alternative use for a model with fast and slow weights to address the problem of arbitration between two systems of control. This novel approach is capable of combining the benefits of model free and model based learning in one simple model, without need for a homunculus and may have important implications in addressing how both goal directed and stimulus response learning may coexist. Modelling cortical-subcortical loops offers the potential of incorporating both the symptoms and cognitive deficits associated with schizophrenia by taking into account the interactions between midbrain/striatum and cortical areas.