TY - JOUR
T1 - Interactions between hippocampal activity and striatal dopamine in people at clinical high risk for psychosis: relationship to adverse outcomes
AU - Modinos, Gemma
AU - Richter, Anja
AU - Egerton, Alice
AU - Bonoldi, Ilaria
AU - Azis, Matilda
AU - Antoniades, Mathilde
AU - Bossong, Matthijs
AU - Crossley Karmelic, Nicolas
AU - Perez, Jesus
AU - Stone, James
AU - Veronese, Mattia
AU - Zelaya, Fernando
AU - Grace, Anthony A
AU - Howes, Oliver
AU - Allen, Paul
AU - McGuire, Philip
N1 - Funding Information:
This work was supported by a Wellcome Trust Program Grant to PM, PA, ODH, JS, and AAG (grant number 091667, 2011), and an MRC Research Grant to PM (grant number G0700995). GM is supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant number 202397/Z/ 16/Z). Dr. Grace receives consulting fees from Johnson & Johnson, Lundbeck, Pfizer, GSK, Merck, Takeda, Dainippon Sumitomo, Otsuka, Lilly, Roche, Asubio, and Abbott; and receives research funding from Lundbeck, Lilly, Autifony, Alkermes, and Johnson & Johnson. Dr. Howes has received investigator-initiated research funding from and/or participated in advisory/speaker meetings organized by Astra-Zeneca, Autifony, BMS, Eli Lilly, Heptares, Invicro, Jansenn, Lundbeck, Lyden-Delta, Otsuka, Servier, Suno-vion, Rand, and Roche. Neither Dr. Howes or his family have been employed by or have holdings/a financial stake in any biomedical company. The other authors declare no competing financial interests.
Publisher Copyright:
© 2021, The Author(s).
PY - 2021/5/3
Y1 - 2021/5/3
N2 - Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal 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 labeling 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) (p
fwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p
fwe = 0.035); the association was negative in CHR with poor outcomes (p
fwe = 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.
AB - Preclinical models propose that increased hippocampal activity drives subcortical dopaminergic dysfunction and leads to psychosis-like symptoms and behaviors. Here, we used multimodal 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 labeling 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) (p
fwe = 0.026). The relationship between rCBF in this right hippocampal region and striatal dopamine synthesis capacity was also significantly different between groups (p
fwe = 0.035); the association was negative in CHR with poor outcomes (p
fwe = 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.
UR - http://www.scopus.com/inward/record.url?scp=85105298891&partnerID=8YFLogxK
U2 - 10.1038/s41386-021-01019-0
DO - 10.1038/s41386-021-01019-0
M3 - Article
SN - 0893-133X
VL - 46
SP - 1468
EP - 1474
JO - Neuropsychopharmacology
JF - Neuropsychopharmacology
IS - 8
ER -