The relationship between grey matter volume and striatal dopamine function in psychosis: a multimodal 18F-DOPA PET and voxel-based morphometry study

• Published in: Molecular psychiatry 2021-04, Vol.26 (4), p.1332-1345
• Main Authors: D’Ambrosio, Enrico, Jauhar, Sameer, Kim, Seoyoung, Veronese, Mattia, Rogdaki, Maria, Pepper, Fiona, Bonoldi, Ilaria, Kotoula, Vasileia, Kempton, Matthew J., Turkheimer, Federico, Kwon, Jun Soo, Kim, Euitae, Howes, Oliver D.
• Format: Article
• Language: English
• Subjects: 59/57; 59/78; 631/378; 692/699/476/1799; Behavioral Sciences; Biological Psychology; Dihydroxyphenylalanine; Dopamine; Dopamine receptors; Hypotheses; Magnetic resonance imaging; Medicine; Medicine & Public Health; Mental disorders; Morphometry; Neostriatum; Neurosciences; Pharmacotherapy; Positron emission tomography; Prefrontal cortex; Psychiatry; Psychosis; Schizophrenia; Substantia grisea
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/s41380-019-0570-6

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 18 F-DOPA PET scans to measure dopamine synthesis capacity (indexed as the influx rate constant K i cer ) 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 K i cer . 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.