Tubiolo Philip N, Williams John C, Gil Roberto B, Cassidy Clifford, Haubold Natalka K, Patel Yash, Abeykoon Sameera K, Zheng Zu Jie, Pham Dathy T, Ojeil Najate, Bobchin Kelly, Silver-Frankel Eilon B, Perlman Greg, Weinstein Jodi J, Kellendonk Christoph, Horga Guillermo, Slifstein Mark, Abi-Dargham Anissa, Van Snellenberg Jared X
Department of Biomedical Engineering, Stony Brook University, Stony Brook, NY 11794.
Department of Psychiatry and Behavioral Health, Renaissance School of Medicine at Stony Brook University, Stony Brook, NY 11794.
medRxiv. 2025 Apr 1:2025.03.31.25324962. doi: 10.1101/2025.03.31.25324962.
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.
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.
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.
fMRI and NM-MRI were collected at New York State Psychiatric Institute. [C]-(+)-PHNO PET was collected at Yale University.
Participants were aged 18-55, and demographically matched. PSZ were antipsychotic drug-naïve or drug-free for at least three weeks prior to recruitment.
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 [C]-(+)-PHNO PET with amphetamine challenge. PSZ displayed elevated task-state FC (0.11±0.10 versus 0.05±0.09 in HC; =0.0252), which was associated with increased NM-MRI contrast ratio (β* [SE] = 0.40 [0.17]; =0.023), decreased baseline D2 receptor availability (β* [SE] = -0.45 [0.17]; =0.039), greater amphetamine-induced dopamine release (β* [SE] = -0.82 [0.27]; =0.021), and worse task performance (β* [SE] = -0.31 [0.13]; =0.020).
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.
在先前的研究中，精神分裂症患者（PSZ）中观察到的纹状体多巴胺功能障碍的转基因小鼠模型在基底神经节中表现出与多巴胺相关的神经可塑性。这种表型从未在人类PSZ中得到证实。
通过基于任务和静息态功能磁共振成像（fMRI）、神经黑色素敏感磁共振成像（NM-MRI）和正电子发射断层扫描（PET），确定未用药的PSZ中基底神经节连接性的特定多巴胺相关改变。
这项针对未用药的PSZ和健康对照（HC）的病例对照研究于2014年11月至2018年6月进行，分析于2023年4月至2025年2月进行。
fMRI和NM-MRI在纽约州精神病研究所收集。[C]-(+)-PHNO PET在耶鲁大学收集。
参与者年龄在18-55岁之间，人口统计学特征匹配。PSZ在招募前至少三周未使用抗精神病药物或已停药。
1）背侧尾状核（DCa）与外侧苍白球（GPe）之间的任务态和静息态功能连接（FC），2）与精神病症状严重程度相关的黑质体素中的NM-MRI对比率，3）DCa中[C]-(+)-PHNO结合潜能的基线和苯丙胺诱导的变化。
37名PSZ（平均±标准差年龄，32.7±12.7岁，29.7%为女性）和30名HC（32.5±9.7岁，26.7%为女性）接受了静息态fMRI；29名PSZ（33.4±12.7岁，31%为女性）和29名HC（32.4±9.7岁，31%为女性）接受了基于工作记忆任务的fMRI。22名PSZ（35.1±13.9岁，36.4%为女性）和20名HC（29.4±8.5岁，35%为女性）接受了NM-MRI。7名PSZ（23.1±6.3岁，57.1%为女性）和4名HC（31.5±11.9岁，25%为女性）接受了苯丙胺激发的[C]-(+)-PHNO PET。PSZ表现出任务态FC升高（HC为0.11±0.10，PSZ为0.05±0.09；P = 0.0252），这与NM-MRI对比率增加（β*[标准误]= 0.40[0.17]；P = 0.023）、基线D2受体可用性降低（β*[标准误]= -0.45[0.17]；P = 0.039）、更大的苯丙胺诱导的多巴胺释放（β*[标准误]= -0.82[0.27]；P = 0.021）以及更差的任务表现（β*[标准误]= -0.31[0.13]；P = 0.020）相关。
本研究提供了未用药的PSZ中DCa和GPe连接性与多巴胺相关的神经异常的体内证据。这种表型提示了精神分裂症工作记忆缺陷的潜在神经发育机制，代表了开发认知缺陷治疗方法的关键一步。
