Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function

TY - JOUR

T1 - Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function

AU - Allen, Paul

AU - Hird, Emily J.

AU - Orlov, Natasza

AU - Modinos, Gemma

AU - Bossong, Matthijs

AU - Antoniades, Mathilde

AU - Sampson, Carly

AU - Azis, Matilda

AU - Howes, Oliver

AU - Stone, James

AU - Perez, Jesus

AU - Broome, Matthew

AU - Grace, Antony A.

AU - McGuire, Philip

N1 - Funding Information: This research was funded in whole, or in part, by the Wellcome Trust [grant 091667/ Z/10/Z]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. This study was supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, Maudsley NHS Foundation Trust and King’s College London. EJH is funded by the Medical Research Council (Grant No. MC-A656-5QD30, Grant No. MC_PC_17214) GM is funded by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (#202397/Z/ 16/Z). AG is funded by USPHS MH57440. MB was supported by a Veni fellowship from the Netherlands Organization for Scientific Research. Funding Information: A.G. receives research funding from Alkermes, Lundbeck, and receives consulting fees from Takeda, Roche, Lyra, and Concert. 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 ODH or his family have been employed by or have holdings/a financial stake in any biomedical company. Publisher Copyright: © 2021, The Author(s).

PY - 2021/12

Y1 - 2021/12

N2 - Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

AB - Preclinical rodent models suggest that psychosis involves alterations in the activity and glutamatergic function in the hippocampus, driving dopamine activity through projections to the striatum. The extent to which this model applies to the onset of psychosis in clinical subjects is unclear. We assessed whether interactions between hippocampal glutamatergic function and activity/striatal connectivity are associated with adverse clinical outcomes in people at clinical high-risk (CHR) for psychosis. We measured functional Magnetic Resonance Imaging of hippocampal activation/connectivity, and 1H-Magnetic Resonance Spectroscopy of hippocampal glutamatergic metabolites in 75 CHR participants and 31 healthy volunteers. At follow-up, 12 CHR participants had transitioned to psychosis and 63 had not. Within the clinical high-risk cohort, at follow-up, 35 and 17 participants had a poor or a good functional outcome, respectively. The onset of psychosis (ppeakFWE = 0.003, t = 4.4, z = 4.19) and a poor functional outcome (ppeakFWE < 0.001, t = 5.52, z = 4.81 and ppeakFWE < 0.001, t = 5.25, z = 4.62) were associated with a negative correlation between the hippocampal activation and hippocampal Glx concentration at baseline. In addition, there was a negative association between hippocampal Glx concentration and hippocampo-striatal connectivity (ppeakFWE = 0.016, t = 3.73, z = 3.39, ppeakFWE = 0.014, t = 3.78, z = 3.42, ppeakFWE = 0.011, t = 4.45, z = 3.91, ppeakFWE = 0.003, t = 4.92, z = 4.23) in the total CHR sample, not seen in healthy volunteers. As predicted by preclinical models, adverse clinical outcomes in people at risk for psychosis are associated with altered interactions between hippocampal activity and glutamatergic function.

UR - http://www.scopus.com/inward/record.url?scp=85118887429&partnerID=8YFLogxK

U2 - 10.1038/s41398-021-01705-z

DO - 10.1038/s41398-021-01705-z

M3 - Article

C2 - 34759289

AN - SCOPUS:85118887429

SN - 2158-3188

VL - 11

JO - Translational psychiatry

JF - Translational psychiatry

IS - 1

M1 - 579

ER -