Translational Evidence for Dopaminergic Rewiring of the Basal Ganglia in Persons with Schizophrenia
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Background
In prior work, a transgenic mouse model of striatal dopamine dysfunction observed in persons with schizophrenia (PSZ) exhibited dopamine-related neuroplasticity in the basal ganglia, a phenotype that has never been demonstrated in human PSZ. Consequently, we sought to identify a dopamine-related alteration of basal ganglia connectivity via working memory task-based and resting-state functional magnetic resonance imaging (fMRI), neuromelanin-sensitive MRI (NM-MRI), and positron emission tomography (PET), in unmedicated PSZ.
Methods
In this case-control study, 37 unmedicated PSZ and 30 demographically matched healthy controls (HC) underwent resting-state fMRI; a subset of 29 PSZ and 29 HC also underwent working memory task-based fMRI. Additionally, 22 PSZ and 20 HC underwent NM-MRI and 7 PSZ and 4 HC underwent [ 11 C]-(+)-PHNO PET with amphetamine challenge. Primary outcome measures included: 1) task-state and resting-state functional connectivity (FC) between dorsal caudate (DCa) and globus pallidus externus (GPe), 2) NM-MRI contrast-to-noise ratio in substantia nigra/ventral tegmental area voxels associated with psychotic symptom severity, and 3) baseline and amphetamine-induced change in [ 11 C]-(+)-PHNO binding potential in DCa.
Results
PSZ displayed elevated DCa-GPe task-state FC, which was associated with increased NM-MRI contrast-to-noise ratio in the substantia nigra, decreased baseline DCa D2 receptor availability, greater amphetamine-induced DCa dopamine release, and worse working memory task performance.
Conclusions
This study provides in-vivo evidence of a dopamine-associated neural abnormality of DCa and GPe connectivity in unmedicated PSZ. This phenotype suggests a potential neurodevelopmental mechanism of working memory deficits in schizophrenia, representing a critical step towards developing treatments for cognitive deficits.
