Translational Evidence for Dopaminergic Alteration of Basal Ganglia Functional Connectivity in Persons with Schizophrenia

In prior work, a transgenic mouse model of striatal dopamine dysfunction observed in persons with schizophrenia (PSZ) exhibited dopamine-related neuroplasticity of axonal projections in 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. 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, and another subset of 22 PSZ and 20 HC underwent NM-MRI. Primary outcome measures included: 1) task-state and resting-state functional connectivity (FC) between dorsal caudate (DCa) and globus pallidus externus (GPe), and 2) NM-MRI contrast-to-noise ratio in substantia nigra/ventral tegmental area voxels associated with psychotic symptom severity. PSZ displayed elevated DCa-GPe task-state FC, which was associated with increased NM-MRI contrast-to-noise ratio in the substantia nigra and worse working memory task performance. This in-vivo evidence of a dopamine-associated neural abnormality of DCa and GPe FC in unmedicated PSZ suggests a potential neurodevelopmental mechanism of working memory deficits in schizophrenia, which could be a critical step towards developing treatments for cognitive deficits.