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[Preprint]. 2025 Apr 1:2025.03.31.25324962.
doi: 10.1101/2025.03.31.25324962.

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

Philip N Tubiolo  1   2   3 , John C Williams  1   2   4 , Roberto B Gil  2   5   6 , Clifford Cassidy  2 , Natalka K Haubold  2 , Yash Patel  2 , Sameera K Abeykoon  2 , Zu Jie Zheng  2   7 , Dathy T Pham  2   8 , Najate Ojeil  5   6 , Kelly Bobchin  2 , Eilon B Silver-Frankel  2 , Greg Perlman  2 , Jodi J Weinstein  2   5   6 , Christoph Kellendonk  5   6   9 , Guillermo Horga  5   6 , Mark Slifstein  2   5   6 , Anissa Abi-Dargham  1   2   5   6   10 , Jared X Van Snellenberg  1   2   5   6   11
Affiliations

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

Philip N Tubiolo et al. medRxiv. .

Abstract

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.

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Conflict of interest statement

Competing Interests Drs. Cassidy and Horga are inventors on patents for the analysis of NM-MRI, licensed to Terran Biosciences, Inc., but have received no royalties. Drs. Cassidy and Horga have an investigator-initiated sponsored research agreement and a licensing agreement with Terran Biosciences, Inc. Dr. Slifstein reports having served as a paid consultant for Neurocrine Biosciences, Inc. and for Yale University. Dr. Abi-Dargham received consulting fees from Neurocrine Biosciences, Inc., from Abbvie, Inc., and from MapLight Therapeutics, Inc. Dr. Abi-Dargham holds stock options in Herophilus, Inc. and in Terran Biosciences, Inc. Dr. Abi-Dargham is a Deputy Editor for the journal Biological Psychiatry. All other authors report no competing interests.

Figures

Figure 1.
Figure 1.
Schematic of basal ganglia-thalamo-cortical circuitry, highlighting glutamatergic (green arrows), GABAergic (red and orange arrows), and dopaminergic (blue arrows) connections between regions. Orange dashed line represents bridging collateral axonal projections from the associative striatum (primarily dorsal caudate) to the globus pallidus externus (GPe). GPi = globus pallidus internus; STN = subthalamic nucleus; SNr = substantia nigra pars reticulata; SNc = substantia nigra pars compacta; VTA = ventral tegmental area.
Figure 2.
Figure 2.
Probability density of A) dorsal caudate (DCa) and B) globus pallidus externus (GPe) regions of interest in the task-based fMRI sample (N = 58), as well as group differences in DCa-GPe resting-state functional connectivity (rs-FC; panel C) and task-state functional connectivity (ts-FC; panel D) between healthy controls (HC) and persons with schizophrenia (PSZ). Long-dashed and short-dashed lines denote median and interquartile range in panel C (due to non-normal data) and means and standard deviations in panel D. FC was calculated controlling for the average timeseries in dorsolateral prefrontal cortex, globus pallidus internus, substantia nigra, and mediodorsal nucleus.
Figure 3.
Figure 3.
A) Average neuromelanin-sensitive MRI (NM-MRI) contrast-to-noise ratio (CNR) across all participants (N = 42). B) Association between average NM-MRI CNR in the voxels shown in panel A and task-state functional connectivity (ts-FC) between dorsal caudate (DCa) and globus pallidus externus (GPe), controlling for age, biological sex, and diagnosis. Associations between C) [11C]-(+)-PHNO Baseline BPND or D) ΔBPND following amphetamine challenge and DCa-GPe ts-FC controlling for age, biological sex, and diagnosis. Regression plot inlay shows standardized regression coefficient β*.
Figure 4.
Figure 4.
Associations between working memory capacity K calculated from self-ordered working memory task (SOT) performance (panel A), Positive and Negative Syndrome Scale (PANSS) positive symptom score (panel B), or PANSS negative symptom score (panel C), and task-state functional connectivity (ts-FC) between dorsal caudate (DCa) and globus pallidus externus (GPe). Associations between K and DCa-GPe ts-FC were calculated in all participants (N = 58) controlling for age, biological sex, and diagnosis, while PANSS symptom associations were calculated in persons with schizophrenia (PSZ) only, controlling for age and biological sex. Plot inlays shows standardized regression coefficient β*.
See this image and copyright information in PMC

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