Brain mechanisms of impaired episodic memory in schizophrenia

精神分裂症情景记忆受损的脑机制

• 批准号: 7885671
• 负责人: John D Ragland
• 金额: $ 34.43万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-17 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7885671
• 关键词: Address; Area; Behavioral; Binding; Brain; Categories; Clinical; Clinical Trials; Cognitive; Data; Development; Disease; Episodic memory; Eye Movements; Familiarity; Female; Functional Magnetic Resonance Imaging; Functional disorder; Gender; Hippocampus (Brain); Individual; Learning; Measures; Memory; Memory impairment; Motivation; Neurobiology; Neurocognitive; Outcome; Outcome Measure; Patients; Pattern; Performance; Prefrontal Cortex; Process; Quality of life; Rehabilitation therapy; Relative (related person); Research; Retrieval; Role; Schizophrenia; Semantics; Short-Term Memory; Social Functioning; Symptoms; Task Performances; Testing; Time; Translational Research; Treatment outcome; Voice; Work; base; cognitive enhancement; cognitive function; drug development; functional disability; functional outcomes; inattention; insight; long term memory; male; memory retrieval; neurobiological mechanism; neuroimaging; neuromechanism; neuropsychological; novel; public health relevance; relating to nervous system; relational memory; remediation; research study; theories; therapy development

DESCRIPTION (provided by applicant): Episodic long-term memory (LTM) is among the most severely impaired cognitive domains in schizophrenia, and is also one of the strongest predictors of long-term functional outcome in the illness. Patients with better episodic memory also tend to have better rehabilitative treatment outcome, better work and social role functioning, and higher quality of life. Unfortunately, memory deficits are largely unaffected by our currently available treatments, and new treatments are not yet established. The current proposal aims to identify neurobiological mechanisms of relative strengths and weaknesses in episodic memory function in patients with schizophrenia to provide targets for new treatment development. The proposed research tests the novel theory that, in new learning situations, patients with schizophrenia are specifically impaired in their ability to engage dorsolateral prefrontal (DLPFC) and hippocampal mechanisms necessary for processing items of information in relation to each other while forming and retrieving long-term memories. During memory formation, patients are predicted to have trouble engaging strategies that emphasize relationships amongst items in working memory (i.e., a DLPFC working memory (WM) control deficit), and also to fail at establishing long-term memories of the relationship between items and the context in which they are encountered (i.e., a hippocampal relational binding deficit). In contrast, patients' ability to engage the ventrolateral prefrontal cortex (VLPFC) to maintain individual items in WM and their ability to engage the perirhinal cortex (PRc) to form individual item representations in LTM is predicted to be intact. During memory retrieval, patients are hypothesized to show a similar relational deficit, with retrieval based more upon the memory strength of individual items (i.e., familiarity- based recognition) and less on retrieval of the relational context in which items were encountered (i.e., recollection). Novel behavioral and eye movement memory paradigms along with functional magnetic resonance imaging (fMRI) will address three specific aims:1) To use behavioral and eye movement measures to test the hypothesis that patients have a specific deficit in relational memory, whereas their item memory is intact. 2) To use functional magnetic resonance imaging (fMRI) to test the hypothesis that relational memory deficits in schizophrenia are associated with reduced activity and connectivity of the DLPFC and hippocampus, whereas activity in the VLPFC and PRc is intact. 3) To investigate the relationship between memory performance, DLPFC and hippocampal dysfunction and measures of clinical symptoms and functional disability in patients with schizophrenia. Successful completion of this research will provide new insights into the cognitive and neural mechanisms underlying LTM deficits in schizophrenia; will generate evidence that these mechanisms represent a specific deficit in relational memory and not solely a generalized deficit arising from general inattention, poor motivation or task engagement, etc.; will identify conditions in which there are areas of preserved cognitive function that can be harnessed for remediation efforts; and will identify clinical, cognitive, neural, and functional outcome correlates of memory impairment that can become targets for new drug development and outcome measures to facilitate existing cognitive enhancement clinical trials. PUBLIC HEALTH RELEVANCE: Schizophrenia is characterized by severe memory deficits that compromise daily psycho-social function and limit long-term outcome. This research proposes to use behavioral, fMRI, and eye movement experiments to test a novel theory about a neurocognitive mechanism that can explain memory strengths and weaknesses in the disorder and, thereby, identify target mechanisms for development of new pro-cognitive agents.

描述（由申请人提供）：情节长期记忆（LTM）是精神分裂症中最严重受损的认知领域之一，也是疾病长期功能结果的最强预测指标之一。具有更好记忆力的患者还倾向于具有更好的康复治疗结果，更好的工作和社会角色功能以及更高的生活质量。不幸的是，记忆缺陷在很大程度上不受我们当前可用的治疗的影响，尚未确定新的治疗方法。当前的提案旨在确定精神分裂症患者的情节记忆功能相对强度和弱点的神经生物学机制，以提供新的治疗发展的靶标。拟议的研究检验了一种新理论，在新的学习情况下，精神分裂症患者的参与性前额叶（DLPFC）和海马机制的能力特别受损术语记忆。在记忆形成期间，预计患者会遇到困难的策略，这些策略强调工作记忆中项目之间的关系（即DLPFC工作记忆（WM）控制缺陷），并且无法在项目与项目之间的关系和项目之间建立长期记忆。它们遇到的上下文（即海马关系结合缺陷）。相比之下，患者参与腹外侧前额叶皮层（VLPFC）的能力可以保持WM中的单个项目，并且预计将与LTM中形成单个项目表示的能力完好无损。在记忆检索过程中，假设患者显示出类似的关系赤字，检索更多基于单个项目的记忆力（即基于熟悉的识别），而对遇到项目的关系环境的检索较少（即回忆（即，是） ）。新颖的行为和眼动记忆范例以及功能磁共振成像（fMRI）将解决三个特定的目标：1）使用行为和眼动措施测试患者在关系记忆中具有特定缺陷的假设，而他们的项目记忆是完好无损的。 2）使用功能磁共振成像（fMRI）来检验以下假设：精神分裂症中的关系记忆缺陷与DLPFC和HAPPOCAMPUS的活性降低和连通性有关，而VLPFC和PRC的活性是完整的。 3）研究精神分裂症患者的记忆性能，DLPFC和海马功能障碍与临床症状和功能障碍的措施之间的关系。这项研究的成功完成将为精神分裂症LTM缺陷的认知和神经机制提供新的见解。将产生证据表明这些机制代表了关系记忆中的特定赤字，而不仅仅是由于普遍的注意力不集中，动机或任务参与等而引起的普遍赤字。将确定可以利用保留的认知功能领域进行修复工作的条件；并将确定记忆障碍的临床，认知，神经和功能结果相关性，这些结局可能成为新药开发和结果指标的目标，以促进现有的认知增强临床试验。 公共卫生相关性：精神分裂症的特征是严重的记忆缺陷，这些缺陷会损害日常的心理社会功能并限制长期结局。这项研究建议使用行为，功能磁共振成像和眼动实验来测试有关神经认知机制的新理论，该理论可以解释该疾病中的记忆强度和缺点，从而确定了用于发展新的培养认知药物的目标机制。