Cortical-Striatal Dysfunction and Vulnerability to Schizophrenia

皮质纹状体功能障碍和精神分裂症的易感性

• 批准号: 7103567
• 负责人: ROBERT F ASARNOW
• 金额: $ 35.23万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-08-01 至 2008-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7103567
• 关键词: adolescence (12-20); behavior test; behavioral /social science research tag; brain disorders; caudate nucleus; child mental disorders; cingulate gyrus; clinical research; family genetics; functional magnetic resonance imaging; human subject; morphometry; motor cortex; neuropathology; neuropsychological tests; neuropsychology; prefrontal lobe /cortex; psychometrics; psychopathology; putamen; reinforcer; schizophrenia; short term memory; siblings; substantia nigra; tegmentum

DESCRIPTION (provided by applicant): This project will test the hypothesis that specific cortical-striatal circuits are dysfunctional in schizophrenia. While there is evidence of striatal dysfunction in the few relevant studies of schizophrenia patients, the effect of schizophrenia on striatal functioning was inextricably confounded with the effects of the anti-psychotic medications used to treat schizophrenia. This project will avoid this pitfall by studying two groups of adolescents with liability to schizophrenia (patients with prodromal symptoms of schizophrenia and siblings of patients with childhood onset of schizophrenia), but who are not psychotic and therefore not treated with anti-psychotic medications. Prior research, including ours, suggests that the cognitive DLPFC/Caudate and the "reward" anterior cingulate/ventral striatum and LOF/ventral caudate circuits are impaired in schizophrenia, while the motor cortex/putamen circuit is intact. A combination of skill learning tasks and fMRI will be used to test this hypothesis. In the first year of the grant we will develop a reward-processing task that separately evaluates the effect of reward magnitude and reward predictability on fMRI activation and develop cognitive habit and motor skill learning tasks with comparable psychometric properties. In the second and third years of the grant we will conduct a large-scale pilot study of 20 siblings of childhood onset schizophrenia patients, 40 patients with prodromal symptoms of schizophrenia, and 20 adolescent controls. We will test the hypothesis that skill learning performance and fMRI indices of dysfunction of different cortical-striatal dysfunction will correlate with distinctive clinical features, neuropsychological deficits, and functional outcomes in individuals with liability to schizophrenia, depending on the putative circuit affected. This is the first schizophrenia study to: 1) use the convergence of evidence from psychometrically matched tasks and fMRI activation to test hypotheses about impairments of specific striatal circuits, 2) separately evaluate the effects of reward magnitude and predictability on brain activity, 3) demonstrate that specific cortical-striatal impairments are not due to the effects of anti-psychotic medication by studying adolescents with vulnerability to schizophrenia who have never been psychotic and therefore are not treated with antipsychotic medications.

描述（由申请人提供）：该项目将检验精神分裂症中特定皮质纹状体回路功能失调的假设。虽然在精神分裂症患者的少数相关研究中存在纹状体功能障碍的证据，但精神分裂症对纹状体功能的影响与用于治疗精神分裂症的抗精神病药物的作用不可避免地混淆。该项目将通过研究两组易患精神分裂症的青少年（有精神分裂症前驱症状的患者和儿童期发病的精神分裂症患者的兄弟姐妹）来避免这一陷阱，但他们没有精神病，因此没有接受抗精神病药物治疗。之前的研究（包括我们的研究）表明，精神分裂症患者的认知 DLPFC/尾状核和“奖励”前扣带回/腹侧纹状体和 LOF/腹侧尾状核回路受损，而运动皮层/壳核回路完好无损。技能学习任务和功能磁共振成像的结合将被用来检验这一假设。在资助的第一年，我们将开发一项奖励处理任务，分别评估奖励幅度和奖励可预测性对功能磁共振成像激活的影响，并培养具有可比心理测量特性的认知习惯和运动技能学习任务。在拨款的第二年和第三年，我们将对 20 名儿童期发病的精神分裂症患者的兄弟姐妹、40 名有精神分裂症前驱症状的患者和 20 名青少年对照者进行大规模试点研究。我们将检验以下假设：不同皮质纹状体功能障碍的技能学习表现和功能磁共振成像指数将与易患精神分裂症的个体的独特临床特征、神经心理缺陷和功能结果相关，具体取决于受影响的假定回路。这是第一项精神分裂症研究：1) 使用心理测量匹配任务和功能磁共振成像激活的证据来检验有关特定纹状体回路损伤的假设，2) 分别评估奖励幅度和可预测性对大脑活动的影响，3) 证明通过研究易患精神分裂症的青少年，他们从未患过精神病，因此未接受过治疗，表明特定的皮质纹状体损伤不是由抗精神病药物的作用引起的抗精神病药物。