Cerebellar dysfunction in schizophrenia

精神分裂症的小脑功能障碍

• 批准号: 8438844
• 负责人: WILLIAM P HETRICK
• 金额: $ 38.72万
• 依托单位: TRUSTEES OF INDIANA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-05-05 至 2017-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8438844
• 关键词: Address; Age; Area; Basal Ganglia; Behavior; Behavioral; Blinking; Brain; Brain region; Cerebellar Diseases; Cerebellum; Cerebrum; Clinical; Cognition; Cognitive; Cognitive deficits; Data; Dependence; Development; Diffusion Magnetic Resonance Imaging; Disease; Employee Strikes; Exhibits; Failure; Feedback; Fingers; Functional Magnetic Resonance Imaging; Functional disorder; Funding; Human; Impairment; Individual; Investigation; Knowledge; Lead; Learning; Link; Lobule; Magnetic Resonance Imaging; Measures; Mental disorders; Modeling; Motor; Neurobehavioral Manifestations; Parietal Lobe; Patients; Performance; Play; Process; Psyche structure; Publications; Regression Analysis; Relative (related person); Research; Resolution; Rest; Risk Marker; Role; Schizophrenia; Schizotypal Personality Disorder; Siblings; Structure; Symptoms; Task Performances; Testing; Thalamic structure; Time; Time Perception; base; case-by-case basis; classical conditioning; cognitive function; conditioning; density; endophenotype; frontal lobe; gray matter; improved; innovation; insight; knowledge of results; neuroimaging; neuromechanism; novel; research study; role model; sex; white matter

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. PUBLIC HEALTH RELEVANCE: This study will lead to improved understanding of the neural mechanisms underlying schizophrenia, which is an extraordinarily debilitating psychological disorder. The resulting knowledge will be especially informative about the role of an understudied region of the human brain called the cerebellum, and may lead to the identification and development of innovative treatments.

描述（由申请人提供）：该项目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）与学习和时间处理缺陷有关，与小脑（CB）（CB）和相关电路相关的时间处理缺陷有关。在随后的几年中，我们发现在几个依赖CB依赖性任务的行为功能障碍的SZ中，有惊人的经验证据，包括关联学习（Eykeblink调节），运动正时（手指敲击）和时间感知（时间分配）。此外，我们发现SZ患者和精神分裂型人格障碍患者的一级亲戚也表现出联想学习缺陷。最后，依赖CB依赖性任务的性能与认知功能的相关性支持CB在认知中的作用的当代模型。综上所述，我们的学习和时间处理缺陷的发现优雅地与SZ结构和功能性CB异常的新证据相吻合，并出于几个重要原因保证进一步研究。首先，我们必须确定观察到的行为缺陷是否与功能和结构CB异常的直接证据有关。我们将使用fMRI调查与任务相关的CB激活是否在三个任务中可以预测SZ中SZ中的行为性能缺陷：眼睛闪烁调节，手指敲击和时间分配。其次，确定SZ是否与Cortico-CB连通性受损相关，这一点至关重要。我们将使用MRI检查CB和精选的大脑区域之间的静息状态功能连接性和基于DTI的结构连接性，通常与CB具有较强的神经解剖连接，以至于尚不清楚SZ是否是这种情况，并且被认为与时间处理有关。与任务相关的FMRI动态因果建模将用于研究大脑区域之间的定向影响。第三，了解神经影像学变量是否预测认知表现至关重要，因此我们选择了一系列具有CB参与证据的任务。第四，我们的初步证据表明，在SZ患者的一级亲属和精神分裂症人格障碍中，CB依赖性的眼神调节受到损害，这引起了CB异常是否代表SZ的内向型的问题。有40名SZ和40个一级亲戚将完成一系列任务以解决这些问题。它们的表现将与年龄和性别匹配的非精神病患者进行比较（n = 80）。成功完成拟议的研究将确定：（1）CB功能障碍是否构成了SZ在联想学习和时间处理任务中观察到的行为异常； （2）CB异常是否代表SZ的内表型。我们的数据将严重告知CB参与精神疾病皮质认知加工的模型，并就疾病的潜在新型机制和治疗靶标的见解。 公共卫生相关性：这项研究将导致对精神分裂症基础的神经机制的理解，这是一种非常令人衰弱的心理障碍。由此产生的知识将对人脑的研究被称为小脑的作用特别有用，并可能导致创新治疗的识别和发展。