Mesostriatal Dopaminergic Circuit Dysfunction in Schizophrenia: A Multimodal Neuromelanin-Sensitive Magnetic Resonance Imaging and [18F]-DOPA Positron Emission Tomography Study

Abstract

Background: Striatal hyperdopaminergia is implicated in the pathoetiology of schizophrenia, but how this relates to dopaminergic midbrain activity is unclear. Neuromelanin (NM)-sensitive magnetic resonance imaging provides a marker of long-term dopamine function. We examined whether midbrain NM-sensitive magnetic resonance imaging contrast-to-noise ratio (NM-CNR) was higher in people with schizophrenia than in healthy control (HC) participants and whether this correlated with dopamine synthesis capacity.

Methods: One hundred fifty-four participants (schizophrenia group: n = 74, HC group: n = 80) underwent NM-sensitive magnetic resonance imaging of the substantia nigra and ventral tegmental area (SN-VTA). A subset of the schizophrenia group (n = 38) also received [¹⁸F]-DOPA positron emission tomography to measure dopamine synthesis capacity (K_i^cer) in the SN-VTA and striatum.

Results: SN-VTA NM-CNR was significantly higher in patients with schizophrenia than in HC participants (effect size = 0.38, p = .019). This effect was greatest for voxels in the medial and ventral SN-VTA. In patients, SN-VTA K_i^cer positively correlated with SN-VTA NM-CNR (r = 0.44, p = .005) and striatal K_i^cer (r = 0.71, p < .001). Voxelwise analysis demonstrated that SN-VTA NM-CNR was positively associated with striatal K_i^cer (r = 0.53, p = .005) and that this relationship seemed strongest between the ventral SN-VTA and associative striatum in schizophrenia.

Conclusions: Our results suggest that NM levels are higher in patients with schizophrenia than in HC individuals, particularly in midbrain regions that project to parts of the striatum that receive innervation from the limbic and association cortices. The direct relationship between measures of NM and dopamine synthesis suggests that these aspects of schizophrenia pathophysiology are linked. Our findings highlight specific mesostriatal circuits as the loci of dopamine dysfunction in schizophrenia and thus as potential therapeutic targets.

Keywords: Basal ganglia; Biomarker; Etiology; Mechanism; Psychosis; Subcortex.