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Associations between corticolimbic glutamatergic metabolites and functional connectivity in people at clinical high-risk for psychosis

Overview

Authors: Abigail Gee1, Nicholas R. Livingston1, Amanda Kiemes1,2, Samuel R. Knight1, Paulina B. Lukow1,3, David J. Lythgoe4, Natasha Vorontsova5, Jacek Donocik6, James Davies7, Eugenii A. Rabiner7, Federico Turkheimer4, Matthew B. Wall7, Thomas J. Spencer8,9, Andrea de Micheli8,9, Paolo Fusar-Poli8,9,10, Anthony A. Grace11, Steven C. Williams4, Philip McGuire12,13, Paola Dazzan1,14, Gemma Modinos1,15
15 affiliations
  1. Department of Psychological Medicine, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
  2. Artificial Intelligence Centre for Value-based Healthcare, London, United Kingdom
  3. Institute of Cognitive Neuroscience, University College London, London, United Kingdom
  4. Department of Neuroimaging, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
  5. Southwark Early Intervention Service, South London and the Maudsley NHS Foundation Trust, London, United Kingdom
  6. Lewisham Early Intervention Service, South London and the Maudsley NHS Foundation Trust, London, United Kingdom
  7. Perceptive Inc., Burlington Danes Building, Imperial College London, London, United Kingdom
  8. Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
  9. Outreach and Support in South London (OASIS) Service, South London and the Maudsley NHS Foundation Trust, London, United Kingdom
  10. Department of Brain and Behavioural Sciences, University of Pavia, Pavia, Italy
  11. Departments of Neuroscience, Psychiatry and Psychology, University of Pittsburgh, Pittsburgh, United States
  12. Department of Psychiatry, University of Oxford, Oxford, United Kingdom
  13. NIHR Oxford Health Biomedical Research Centre, University of Oxford, Oxford, United Kingdom
  14. NIHR Maudsley Biomedical Research Centre, King’s College London, London, United Kingdom
  15. MRC Centre for Neurodevelopmental Disorders, Institute of Psychiatry, Psychology & Neuroscience, King’s College London, London, United Kingdom
Dates: published online 8 April 2026
Type: Preprint
License: CC BY
Identifiers: DOI 10.64898/2026.04.08.26350385 · OpenAlex W7152022116
Open access: green, a free copy (OpenAlex)
Status: code on request
Categories: fMRI (modality), human (organism), schizophrenia / psychosis (population), clinical / translational (subfield)
Methods: Spectral & time-frequency, Statistics, Connectivity, fMRI & imaging
Topic: Functional Brain Connectivity Studies (Cognitive Neuroscience, Neuroscience), according to OpenAlex
Funding: Wellcome Trust (202397/Z/16/Z, 223486/Z/21/Z)
Citations: not cited yet (Europe PMC); 49 references in the paper

Abstract

Recent evidence suggests that psychosis involves glutamatergic dysfunction and altered activity/connectivity within corticolimbic circuitry. While altered relationships between corticolimbic glutamatergic metabolite levels and resting-state functional connectivity (FC) have been described in schizophrenia and first-episode psychosis (FEP), whether these disruptions are also present prior to psychosis onset remains unclear. We measured Glx (glutamate + glutamine) levels in the anterior cingulate cortex (ACC) and hippocampus with magnetic resonance spectroscopy (MRS), and resting-state FC between corticolimbic regions of interest (ACC, hippocampus, amygdala and nucleus accumbens (NAc)) in antipsychotic-naïve participants at clinical high-risk for psychosis (CHR-P, n=22), compared to healthy controls (HC, n=23) and FEP participants (n=10). Primary analyses compared corticolimbic Glx-FC interactions between CHR-P and HC groups. FEP individuals were included in secondary Glx comparisons but were excluded from FC analyses due to insufficient sample size after quality control. There was a significant interaction between group and ACC Glx for FC between the NAc and the bilateral amygdala and hippocampus (p-FDR=0.021), which was driven by a significant negative association in the CHR-P group (p-FDR=0.005). Complementary seed-to-whole-brain analyses revealed additional negative associations between ACC Glx and FC with the left middle temporal gyrus, and between hippocampal Glx and FC with the parahippocampal and temporal fusiform cortices in CHR-P individuals, which were absent in HC. FEP showed higher Glx than HC across both regions (p=0.015), but there were no significant Glx differences between CHR-P and HC. These data suggest that increased risk for psychosis is associated with altered relationships between corticolimbic connectivity and glutamatergic function.

Reproduced under the paper's license (CC BY), from the paper cited above.

Code

The paper says that its authors' code is available on request: it was not published with the paper, so there is nothing to verify.

The paper's code and data availability statement is in the Data section.

Tracing map

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Data

No dataset and no data link were found in the paper.

Data Availability Statement

MRS and resting-state fMRI data has been uploaded to an open repository and will be made public upon publication. Other study data and code is available from the corresponding author on reasonable request.

Reproduced under the paper's license (CC BY), from the paper cited above.

Versions

The history of this record: each version stored by the harvester or made by a correction of its authors or of the maintainers of its code, and what changed in its facts. The texts of the paper (its abstract, its availability statements) are not part of it; versions that changed only those are not listed.

Version 1, 29 September 2026: the first record

Recorded: type, journal, dates, 20 authors, 1 funder, 45 references.

Cite

This paper

Gee, A., Livingston, N. R., Kiemes, A., Knight, S. R., Lukow, P. B., Lythgoe, D. J., Vorontsova, N., Donocik, J., Davies, J., Rabiner, E. A., Turkheimer, F., Wall, M. B., Spencer, T. J., de Micheli, A., Fusar-Poli, P., Grace, A. A., Williams, S. C., McGuire, P., Dazzan, P., & Modinos, G. (2026). Associations between corticolimbic glutamatergic metabolites and functional connectivity in people at clinical high-risk for psychosis. medRxiv (preprint). https://doi.org/10.64898/2026.04.08.26350385

BibTeX

@article{gee2026associations,
author = {Gee, Abigail and Livingston, Nicholas R. and Kiemes, Amanda and Knight, Samuel R. and Lukow, Paulina B. and Lythgoe, David J. and Vorontsova, Natasha and Donocik, Jacek and Davies, James and Rabiner, Eugenii A. and Turkheimer, Federico and Wall, Matthew B. and Spencer, Thomas J. and de Micheli, Andrea and Fusar-Poli, Paolo and Grace, Anthony A. and Williams, Steven C. and McGuire, Philip and Dazzan, Paola and Modinos, Gemma},
title = {{Associations between corticolimbic glutamatergic metabolites and functional connectivity in people at clinical high-risk for psychosis}},
journal = {medRxiv (preprint)},
year = {2026},
month = apr,
publisher = {medRxiv},
doi = {10.64898/2026.04.08.26350385},
url = {https://doi.org/10.64898/2026.04.08.26350385}
}

RIS

TY - JOUR
AU - Gee, Abigail
AU - Livingston, Nicholas R.
AU - Kiemes, Amanda
AU - Knight, Samuel R.
AU - Lukow, Paulina B.
AU - Lythgoe, David J.
AU - Vorontsova, Natasha
AU - Donocik, Jacek
AU - Davies, James
AU - Rabiner, Eugenii A.
AU - Turkheimer, Federico
AU - Wall, Matthew B.
AU - Spencer, Thomas J.
AU - de Micheli, Andrea
AU - Fusar-Poli, Paolo
AU - Grace, Anthony A.
AU - Williams, Steven C.
AU - McGuire, Philip
AU - Dazzan, Paola
AU - Modinos, Gemma
TI - Associations between corticolimbic glutamatergic metabolites and functional connectivity in people at clinical high-risk for psychosis
T2 - medRxiv (preprint)
J2 - medRxiv
PY - 2026
DA - 2026/04/08
PB - medRxiv
DO - 10.64898/2026.04.08.26350385
UR - https://doi.org/10.64898/2026.04.08.26350385
ER -

CSL-JSON

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