Cerebellar dysfunction in schizophrenia

描述（由申请人提供）：该项目开始于令人信服的理论证据和有趣的经验提示，以支持我们的创新假设，即精神分裂症（SZ）与小脑（CB）和相关电路功能障碍相关的学习和时间处理缺陷有关。在此期间的几年里，我们发现了惊人的经验证据，在SZ的行为功能障碍的几个CB依赖的任务，包括联想学习（眨眼条件反射），运动计时（手指轻敲），和时间知觉（时间平分）。此外，我们还发现SZ患者和典型人格障碍患者的一级亲属也表现出联想学习障碍。最后，CB依赖的任务和认知功能的性能之间的相关性支持当代模型的CB在认知中的作用。两者合计，我们的研究结果的学习和时间处理赤字吻合优雅的新兴证据的结构和功能CB异常SZ，并值得进一步调查的几个重要原因。首先，我们必须确定所观察到的行为缺陷是否与CB功能和结构异常的直接证据有关。我们将使用功能磁共振成像来研究是否任务相关的CB激活预测行为表现赤字在SZ在三个任务：眨眼条件反射，手指敲击，和时间平分。其次，确定SZ是否与受损的皮质-CB连接相关是至关重要的。我们将使用MRI检查CB和选择的大脑区域之间的静息状态功能连接和基于DTI的结构连接，这些大脑区域通常与CB有很强的神经解剖学连接，尽管尚不清楚SZ是否是这种情况，并且被认为参与了时间处理。任务相关的功能磁共振成像动态因果模型将被用来研究大脑区域之间的方向性影响。第三，了解神经影像学因变量是否能预测认知表现是至关重要的，因此我们选择了一组有强有力证据表明CB参与的任务。第四，我们的初步证据表明，CB依赖性眨眼条件反射在SZ患者的一级亲属和典型人格障碍中受损，这引出了CB异常是否代表SZ的内在表型的问题。40名SZ患者及其40名一级亲属将完成一系列任务来解决这些问题。他们的表现将与年龄和性别匹配的非精神病对照受试者（N=80）进行比较。成功完成拟议的研究将确定：（1）CB功能障碍是否是在SZ中观察到的关于联想学习和时间处理任务的行为异常的基础;以及（2）CB异常是否代表SZ的内在表型。我们的数据将批判性地告知CB参与精神疾病皮层认知处理的模型，并产生有关疾病和治疗靶点的潜在新机制的见解。

DESCRIPTION (provided by applicant): This project began with compelling theoretical evidence and intriguing empirical hints to support our innovative hypothesis that schizophrenia (SZ) is associated with learning and temporal processing deficits linked to dysfunction of the cerebellum (CB) and related circuits. In the intervening years we found striking empirical evidence in SZ of behavioral dysfunction on several CB-dependent tasks, including associative learning (eyeblink conditioning), motor timing (finger tapping), and time perception (temporal bisection). Moreover, we found that 1st-degree relatives of SZ patients and individuals with schizotypal personality disorder also exhibit associative learning deficits. Finally, correlations between performance on CB-dependant tasks and cognitive functioning support contemporary models of the role of the CB in cognition. Taken together, our findings of learning and temporal processing deficits dovetail elegantly with emerging evidence of structural and functional CB abnormalities in SZ, and warrant further investigation for several important reasons. First, we must determine whether the observed behavioral deficits are associated with direct evidence of functional and structural CB abnormalities. We will use fMRI to investigate whether task-related CB activation predicts behavioral performance deficits in SZ across three tasks: eyeblink conditioning, finger tapping, and temporal bisection. Second, it is critical to determine whether SZ is associated with impaired cortico-CB connectivity. We will use MRI to examine resting-state functional connectivity and DTI-based structural connectivity between the CB and select cerebral regions that normally have strong neuroanatomical connections with the CB-though it is not known if this is the case in SZ-and are thought to be involved in temporal processing. Task-related fMRI dynamic causal modeling will be used to study directional influences between brain regions. Third, it is critical to understand whether neuroimaging dependent variables predict cognitive performance, so we have selected a battery of tasks with strong evidence of CB involvement. Fourth, our preliminary evidence that CB-dependent eyeblink conditioning is impaired in 1st-degree relatives of SZ patients and in schizotypal personality disorder begs the question of whether CB abnormalities represent endophenotypes of SZ. Forty individuals with SZ and 40 of their 1st-degree relatives will complete a battery of tasks to address these questions. Their performance will be compared to age- and sex-matched non-psychiatric control subjects (N=80). Successfully completing the proposed research will determine: (1) whether CB dysfunction underlies behavioral abnormalities observed in SZ on associative learning and temporal processing tasks; and (2) whether CB abnormalities represent endophenotypes of SZ. Our data will critically inform models of CB involvement in cortical cognitive processing in psychiatric illness and yield insights about potential novel mechanisms of illness and targets of treatment.