M149. THE TOPOGRAPHY OF STRIATAL DOPAMINE AND SYMPTOMS IN PSYCHOSIS: AN INTEGRATIVE PET AND MRI STUDY

Abstract

Introduction: Striatal dopamine dysfunction is thought to underlie symptoms in psychosis, yet it remains unclear how changes in a single neurotransmitter could underlie the diverse and heterogeneous presentations that are observed in clinical practice. The striatum is a central processing hub, receiving input from almost the entire cortex, and plays a role in sensory, motor, affective, and cognitive processes. Thus, dysfunction in the striatum could plausibly lead to hallucinations, delusions, emotional blunting and other affective symptoms, motor symptoms and cognitive deficits. Given the topographical distribution of cortical inputs, the precise localisation of dopamine dysfunction within the striatum may determine which particular corticostriatal circuits are affected. Aims and Hypotheses: One hypothesis is that the symptomatic consequences of aberrant dopamine signalling vary depending on where within the striatum the dysfunction occurs. We tested this hypothesis using a multimodal imaging approach in 29 unmedicated and minimally-treated patients with first episode psychosis and 21 healthy controls. Method(s): Patients were clinically assessed using the Positive and Negative Syndrome Scale at baseline, and following a minimum of four weeks' treatment with a dopamine antagonist. Each participant was also scanned at baseline using 18F-DOPA positron emission tomography to index striatal dopamine synthesis capacity, and resting state functional MRI to map corticostriatal functional connectivity. For each participant, we used functional connectivity between cortical resting state networks and the striatum to generate individualised connectivity-defined striatal maps. We use these maps to calculate dopamine synthesis capacity for striatal subregions preferentially connected to each cortical network, and investigated whether dopamine function within these different striatal regions showed a relationship with both baseline symptomatology and change in symptoms. Result(s): Fifty participants took part in the study (21 controls and 29 patients). At baseline, mean total PANSS score was 66.7 (SD 20.7). Median time between PET and MRI scan was 15.5 days. Nineteen of the patients received antipsychotic treatment and clinical follow-up. We demonstrated significantly greater orthogonality in our individualised connectivity-based approach compared to standar parcellation methods, which allowed, for the first time to our knowledge, specific subregion-symptom relationship to be investigated. Dopamine synthesis capacity in striatal areas showing strong functional connections to sensorimotor cortex was related to the severity of motor symptoms at baseline (p=0.01), and to the change in motor symptoms following treatment (p=0.001). We also found significant associations between the severity of negative symptoms and striatal dopamine synthesis capacity in striatal regions connected to the default mode network, and between affective symptoms and regions connected to a cinguloopercular cortical network. Conclusion(s): We show that motor retardation associated with schizophrenia is specifically linked to dopamine dysfunction within regions of the striatum linked to the sensorimotor cortex. We also find that dopamine dysfunction within striatal regions linked to the default mode network, and cingulopercular network may relate to negative and affective symptoms respectively. These findings support the hypothesis that the heterogeneity of symptoms in psychosis reflects individual differences in the topography of dopamine dysfunction within the striatum. Disclosure statement: ODH has received investigator-initiated research funding from and/or participated in advisory/ speaker meetings organised by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Sunovion, Rand and Roche. Neither Dr Howes or his family have been employed by or have holdings/ a financial stake in any biomedical company. M.M. has consulted for Cambridge Cognition, Lundbeck and Forum Pharmaceuticals in the past 3 years. He has also received research funding from Takeda, Eli Lilly and Roche. The other authors declare no conflicts of interest. Copyright © 2019