CORTICAL-STRIATAL DYSFUNCTION AND VULNERABILITY TO SCHIZOPHRENIA

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。列出的机构是 研究中心，而研究中心不一定是研究者所在的机构。 这个项目将测试特定的皮质-纹状体回路在精神分裂症中功能失调的假设。虽然在精神分裂症患者的少数相关研究中有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影响不可避免地混淆。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精神分裂症患者的兄弟姐妹）来避免这一陷阱，但他们不是精神病患者，因此没有接受抗精神病药物治疗。先前的研究，包括我们的研究，表明认知DLPFC/尾状核和“奖励”前扣带/腹侧纹状体和LOF/腹侧尾状核电路在精神分裂症中受损，而运动皮层/壳核电路是完整的。结合技能学习任务和功能磁共振成像将被用来测试这一假设。在补助金的第一年，我们将开发一个奖励处理任务，分别评估奖励幅度和奖励可预测性对fMRI激活的影响，并开发具有可比心理测量特性的认知习惯和运动技能学习任务。在第二年和第三年的补助金，我们将进行一项大规模的试点研究的20个兄弟姐妹的儿童发病的精神分裂症患者，40例前驱症状的精神分裂症患者，和20个青少年对照。我们将测试的假设，技能学习性能和功能磁共振成像指标的功能障碍，不同的皮质-纹状体功能障碍将与独特的临床特征，神经心理缺陷，和功能结果的个人精神分裂症的易感性，这取决于假定的电路受影响。这是第一个精神分裂症研究：1）使用来自心理测量匹配任务和fMRI激活的证据的收敛来检验关于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）证明特定的皮质-纹状体损伤不是由于抗-精神病药物通过研究青少年易患精神分裂症，他们从未患过精神病，因此没有接受抗精神病药物治疗。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. 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.