TY - JOUR
T1 - The relationship between grey matter volume and striatal dopamine function in psychosis
T2 - a multimodal 18F-DOPA PET and voxel-based morphometry study
AU - D'Ambrosio, Enrico
AU - Jauhar, Sameer
AU - Kim, Seoyoung
AU - Veronese, Mattia
AU - Rogdaki, Maria
AU - Pepper, Fiona
AU - Bonoldi, Ilaria
AU - Kotoula, Vasileia
AU - Kempton, Matthew J
AU - Turkheimer, Federico
AU - Kwon, Jun Soo
AU - Kim, Euitae
AU - Howes, Oliver D
N1 - Funding Information:
Acknowledgements This research was supported by Medical Research Council (grant MC-A656-5QD30), Maudsley Charity (grant 666), the US Brain & Behaviour Research Foundation, Wellcome Trust (grant 094849/Z/10/Z to Professor Howes), the National Institute for Health Research Biomedical Research Centre at South London and Maudsley National Health Service Foundation Trust, King’s College London, the Seoul National University Bundang Hospital (SNUBH) research Fund (grant 02-2013-010), the National Research Foundation of Korea (grants NRF-2019R1A2C2005500, NRF-2019M3C7A1032472 and 2017M3C7A1029610). Dr Jauhar is supported by a Sim Fellowship, from the Royal College of Physicians, Edinburgh. Dr Veronese is supported by the National Institute for Health Research (NIHR) Biomedical Research Centre at South London and Maudsley NHS Foundation Trust and King’s College London.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
Copyright:
Copyright 2021 Elsevier B.V., All rights reserved.
PY - 2021/4
Y1 - 2021/4
N2 - A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.
AB - A leading hypothesis for schizophrenia and related psychotic disorders proposes that cortical brain disruption leads to subcortical dopaminergic dysfunction, which underlies psychosis in the majority of patients who respond to treatment. Although supported by preclinical findings that prefrontal cortical lesions lead to striatal dopamine dysregulation, the relationship between prefrontal structural volume and striatal dopamine function has not been tested in people with psychosis. We therefore investigated the in vivo relationship between striatal dopamine synthesis capacity and prefrontal grey matter volume in treatment-responsive patients with psychosis, and compared them to treatment non-responsive patients, where dopaminergic mechanisms are not thought to be central. Forty patients with psychosis across two independent cohorts underwent 18F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant Kicer) and structural 3T MRI. The PET, but not MR, data have been reported previously. Structural images were processed using DARTEL-VBM. GLM analyses were performed in SPM12 to test the relationship between prefrontal grey matter volume and striatal Kicer. Treatment responders showed a negative correlation between prefrontal grey matter and striatal dopamine synthesis capacity, but this was not evident in treatment non-responders. Specifically, we found an interaction between treatment response, whole striatal dopamine synthesis capacity and grey matter volume in left (pFWE corr. = 0.017) and right (pFWE corr. = 0.042) prefrontal cortex. We replicated the finding in right prefrontal cortex in the independent sample (pFWE corr. = 0.031). The summary effect size was 0.82. Our findings are consistent with the long-standing hypothesis of dysregulation of the striatal dopaminergic system being related to prefrontal cortex pathology in schizophrenia, but critically also extend the hypothesis to indicate it can be applied to treatment-responsive schizophrenia only. This suggests that different mechanisms underlie the pathophysiology of treatment-responsive and treatment-resistant schizophrenia.
UR - http://www.scopus.com/inward/record.url?scp=85074749750&partnerID=8YFLogxK
U2 - 10.1038/s41380-019-0570-6
DO - 10.1038/s41380-019-0570-6
M3 - Article
C2 - 31690805
SN - 1359-4184
VL - 26
SP - 1332
EP - 1345
JO - Molecular Psychiatry
JF - Molecular Psychiatry
IS - 4
ER -
