Brain mechanisms of impaired episodic memory in schizophrenia

描述（由申请人提供）：情景长期记忆（LTM）是精神分裂症中受损最严重的认知领域之一，也是该疾病长期功能预后的最强预测因素之一。情节记忆较好的患者也往往有较好的康复治疗效果，较好的工作和社会角色功能，以及较高的生活质量。不幸的是，记忆缺陷在很大程度上不受我们目前可用的治疗方法的影响，新的治疗方法尚未建立。目前的建议旨在确定精神分裂症患者情景记忆功能的相对优势和劣势的神经生物学机制，为新的治疗开发提供靶点。这项提议的研究验证了一种新的理论，即在新的学习环境中，精神分裂症患者的背外侧前额叶（DLPFC）和海马体机制在形成和检索长期记忆时处理彼此相关的信息项目的能力特别受损。在记忆形成过程中，预计患者在参与强调工作记忆中项目之间关系的策略方面存在困难（即DLPFC工作记忆（WM）控制缺陷），并且在建立项目与所遇到的环境之间关系的长期记忆方面也失败（即海马关系绑定缺陷）。相比之下，患者使用腹外侧前额叶皮层（VLPFC）维持WM中单个项目的能力，以及他们使用周围皮层（PRc）形成LTM中单个项目表征的能力预计是完整的。在记忆检索过程中，假设患者表现出类似的关系缺陷，检索更多地基于单个项目的记忆强度（即，基于熟悉度的识别），而较少地基于对项目遇到的关系背景的检索（即，回忆）。新的行为和眼动记忆范式以及功能磁共振成像（fMRI）将解决三个具体目标：1)使用行为和眼动测量来检验患者在关系记忆中存在特定缺陷，而他们的项目记忆是完整的假设。2)利用功能性磁共振成像（fMRI）验证精神分裂症患者相关性记忆缺陷与DLPFC和海马的活动和连通性降低有关，而VLPFC和PRc的活动完好无损的假设。3)探讨精神分裂症患者记忆表现、DLPFC与海马功能障碍的关系以及临床症状和功能障碍的测量。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的特定缺陷，而不仅仅是由一般注意力不集中、动机不佳或任务参与等引起的普遍缺陷；将确定在哪些情况下仍有保留的认知功能领域可用于补救工作；并将确定与记忆障碍相关的临床、认知、神经和功能结果，这些结果可以成为新药开发和结果测量的目标，以促进现有的认知增强临床试验。

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.