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

Paul Allen; Emily J. Hird; Natasza Orlov; Gemma Modinos; Matthijs Bossong; Mathilde Antoniades; Carly Sampson; Matilda Azis; Oliver Howes; James Stone; Jesus Perez; Matthew Broome; Antony A. Grace; Philip McGuire

doi:10.1038/s41398-021-01705-z

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

Paul Allen, Emily J. Hird, Natasza Orlov, Gemma Modinos, Matthijs Bossong, Mathilde Antoniades, Carly Sampson, Matilda Azis, Oliver Howes, James Stone, Jesus Perez, Matthew Broome, Antony A. Grace, Philip McGuire

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Abstract

Abstract: 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.

Original language	English
Pages (from-to)	579
Journal	Translational Psychiatry
Volume	11
Issue number	1
Early online date	10 Nov 2021
DOIs	https://doi.org/10.1038/s41398-021-01705-z https://doi.org/10.1038/s41398-021-01705-z
Publication status	Published - 10 Nov 2022

Keywords

Article
/692/53/2423
/692/699/476/1799
/631/378/340
/59/36
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Allen, P., Hird, E. J., Orlov, N., Modinos, G., Bossong, M., Antoniades, M., Sampson, C., Azis, M., Howes, O., Stone, J., Perez, J., Broome, M., Grace, A. A., & McGuire, P. (2022). Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function. Translational Psychiatry, 11(1), 579. https://doi.org/10.1038/s41398-021-01705-z, https://doi.org/10.1038/s41398-021-01705-z

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abstract = "Abstract: 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.",

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author = "Paul Allen and Hird, {Emily J.} and Natasza Orlov and Gemma Modinos and Matthijs Bossong and Mathilde Antoniades and Carly Sampson and Matilda Azis and Oliver Howes and James Stone and Jesus Perez and Matthew Broome and Grace, {Antony A.} and Philip McGuire",

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Allen, P, Hird, EJ, Orlov, N, Modinos, G, Bossong, M, Antoniades, M, Sampson, C, Azis, M, Howes, O, Stone, J, Perez, J, Broome, M, Grace, AA & McGuire, P 2022, 'Adverse clinical outcomes in people at clinical high-risk for psychosis related to altered interactions between hippocampal activity and glutamatergic function', Translational Psychiatry, vol. 11, no. 1, pp. 579. https://doi.org/10.1038/s41398-021-01705-z, https://doi.org/10.1038/s41398-021-01705-z

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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

PY - 2022/11/10

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N2 - Abstract: 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 - Abstract: 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.

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