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A Systems Neuroscience Perspective on Treatment Resistant Schizophrenia: The Role of Cognitive Control, Reinforcement Learning, and Myelination

Student thesis: Doctoral ThesisDoctor of Philosophy

Approximately a third of patients with schizophrenia do not respond to antipsychotic treatment targeting the dopamine system, suggesting that a separable neural dysfunction may drive psychosis in these patients. This thesis aims to probe the mechanisms underlying treatment response by investigating two cognitive processes which have been implicated in schizophrenia – cognitive control and reinforcement learning – as well as brain myelination. The key hypotheses are that 1) treatment resistant schizophrenia emerges due to a failure to exert cognitive control, characterised by prefrontal hypoactivation and functional dysconnectivity, 2) treatment responsive schizophrenia is selectively associated with a subcortical dopaminergic dysfunction, evident in an abnormal neural signature of reward prediction error (RPE) during reinforcement learning, and 3) treatment resistant schizophrenia is characterised by exacerbated structural dysconnectivity as indexed by myelin content. To dissect these mechanisms, performance and neural activation during a cognitive control task and a reinforcement learning task, as well as myelin water fraction (MWF) were compared between 22 treatment resistant patients, 21 treatment responsive patients, and 24 healthy controls. Treatment resistant and responsive patients showed similarly impaired performance on both tasks compared to controls. During the cognitive control task, resistant patients showed an inverse correlation between frontal activation and psychotic symptoms as well as reduced functional fronto-thalamic connectivity compared to controls. During the reinforcement learning task, responsive patients showed reduced cortical and subcortical RPE related activation compared to controls and treatment resistant patients. MWF was reduced in patients compared to controls in several white matter regions but did not differ between the two patient groups. The findings support distinct neural mechanisms underlying treatment resistant and responsive schizophrenia despite similar behaviour. Functional dysconnectivity within the cognitive control network and a deterioration of frontal activation as a function of symptom severity may perpetuate psychosis despite dopaminergic treatment in treatment resistant schizophrenia, although this is not reflected in an exacerbated myelin dysfunction. The results highlight the importance of stratifying patient samples by treatment response status in future research.
Original languageEnglish
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    Award date2018

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