Translational Evidence for Dopaminergic Rewiring of the Basal Ganglia in Persons with Schizophrenia

Importance: In prior work, a transgenic mouse model of the striatal dopamine dysfunction observed in persons with schizophrenia (PSZ) exhibited dopamine-related neuroplasticity in the basal ganglia. This phenotype has never been demonstrated in human PSZ. Objective: To identify a specific dopamine-related alteration of basal ganglia connectivity via task-based and resting-state functional magnetic resonance imaging (fMRI), neuromelanin-sensitive MRI (NM-MRI), and positron emission tomography (PET), in unmedicated PSZ. Design: This case-control study of unmedicated PSZ and healthy controls (HC) occurred between November 2014 and June 2018, with analyses performed between April 2023 and February 2025. Setting: fMRI and NM-MRI were collected at New York State Psychiatric Institute. [11C]-(+)-PHNO PET was collected at Yale University. Participants: Participants were aged 18-55, and demographically matched. PSZ were antipsychotic drug-naïve or drug-free for at least three weeks prior to recruitment. Main Outcomes and Measures: 1) task-state and resting-state functional connectivity (FC) between dorsal caudate (DCa) and globus pallidus externus (GPe), 2) NM-MRI contrast ratio in substantia nigra voxels associated with psychotic symptom severity, and 3) baseline and amphetamine-induced change in [11C]-(+)-PHNO binding potential in DCa. Results: 37 PSZ (mean±SD age, 32.7±12.7 years, 29.7% female) and 30 HC (32.5±9.7 years, 26.7% female) underwent resting-state fMRI; 29 PSZ (33.4±12.7 years, 31% female) and 29 HC (32.4±9.7 years, 31% female) underwent working memory task-based fMRI. 22 PSZ (35.1±13.9 years, 36.4% female) and 20 HC (29.4±8.5 years, 35% female) underwent NM-MRI. 7 PSZ (23.1±6.3 years, 57.1% female) and 4 HC (31.5±11.9 years, 25% female) underwent [11C]-(+)-PHNO PET with amphetamine challenge. PSZ displayed elevated task-state FC (0.11±0.10 versus 0.05±0.09 in HC; P=0.0252), which was associated with increased NM-MRI contrast ratio (β* [SE] = 0.40 [0.17]; P=0.023), decreased baseline D2 receptor availability (β* [SE] = -0.45 [0.17]; P=0.039), greater amphetamine-induced dopamine release (β* [SE] = -0.82 [0.27]; P=0.021), and worse task performance (β* [SE] = -0.31 [0.13]; P=0.020). Conclusions and Relevance: 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.