Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes

Gemma Modinos, Anja Richter, Alice Egerton, Ilaria Bonoldi, Matilda Azis, Mathilde Antoniades, Matthijs G. Bossong, Oliver Howes, J.M. Stone, Fernando Zelaya, Anthony A. Grace, Paul Allen, Philip McGuire

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Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multi-modal neuroimaging to examine the relationship between hippocampal regional cerebral blood flow (rCBF) and striatal dopamine synthesis capacity in people at clinical high risk (CHR) for psychosis, and investigated its association with subsequent clinical and functional outcomes. Ninety-five participants (67 CHR and 28 healthy controls) underwent arterial spin labelling MRI and 18F-DOPA PET imaging at baseline. CHR participants were followed-up for a median of 15 months to determine functional outcomes with the Global Assessment of Function (GAF) scale and clinical outcomes using the Comprehensive Assessment of At Risk Mental States (CAARMS). CHR participants with poor functional outcomes (follow-up GAF<65, n=25) showed higher rCBF in the right hippocampus compared to CHRs with good functional outcomes (GAF≥65, n=25) (pfwe=0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (pfwe=0.035); the association was negative in CHR with poor outcomes (pfwe=0.012), but non-significant in CHR with good outcomes. Furthermore, the correlation between right hippocampal rCBF and striatal dopamine function predicted a longitudinal increase in the severity of positive psychotic symptoms within the total CHR group (p=0.041). There were no differences in rCBF, dopamine, or their associations in the total CHR group relative to controls. These findings indicate that altered interactions between the hippocampus and the subcortical dopamine system are implicated in the pathophysiology of adverse outcomes in the CHR state.
© 2021, G. Modinos, A. Richter, A. Egerton, I. Bonoldi, M. Azis, M. Antoniades, M. Bossong, O. Howes, J. Stone, F. Zeyala, A. Grace, P. Allen, P. McGuire. The attached document (embargoed until 04/11/2021) is an author produced version of a paper published in JOURNAL NAME uploaded in accordance with the publisher’s self-archiving policy. The final published version (version of record) is available online at the link. Some minor differences between this version and the final published version may remain. We suggest you refer to the final published version should you wish to cite from it. 
Original languageEnglish
Publication statusAccepted/In press - 15 Apr 2021

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