Cerebellar dysfunction in schizophrenia

描述(申请人提供)：该项目以令人信服的理论证据和耐人寻味的经验提示开始，以支持我们的创新假设，即精神分裂症(SZ)与学习和时间处理缺陷有关，与小脑(CB)和相关回路的功能障碍有关。在其间的几年中，我们在SZ发现了几个CB依赖任务的行为障碍的显著经验证据，包括联想学习(眨眼条件反射)、运动计时(手指敲击)和时间感知(时间平分)。此外，我们还发现SZ患者的一级亲属和分裂型人格障碍个体也表现出联想学习缺陷。最后，CB依赖任务的成绩与认知功能之间的相关性支持了CB在认知中的作用的当代模型。综上所述，我们的学习和时间加工缺陷的发现与SZ的结构和功能异常的新证据很好地吻合，并基于几个重要原因值得进一步研究。首先，我们必须确定观察到的行为缺陷是否与功能性和结构性CB异常的直接证据有关。我们将使用功能磁共振成像来研究任务相关的CB激活是否可以预测SZ在三个任务中的行为表现缺陷：眨眼条件反射、手指敲击和颞叶分割。其次，确定SZ是否与皮质-CB连接受损有关是至关重要的。我们将使用MRI来检查CB和选定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，这些区域通常与CB有很强的神经解剖学联系-尽管尚不清楚SZ是否如此-并被认为参与了时间处理。与任务相关的fMRI动态因果模型将用于研究大脑区域之间的方向性影响。第三，了解神经成像依赖变量是否可以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，在SZ患者的一级亲属和分裂型人格障碍中，CB依赖的眨眼条件反射受到损害，这就提出了CB异常是否代表SZ的内在表型的问题。40名SZ患者和他们的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控制受试者(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SZ在联想学习和时间加工任务中观察到的行为异常的基础；以及(2)CB异常是否代表SZ的内在表型。我们的数据将为CB参与精神疾病皮质认知过程的模型提供关键信息，并为潜在的新疾病机制和治疗目标提供见解。

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.