Brain mechanisms of impaired episodic memory in schizophrenia

描述(申请人提供)：情节长期记忆(LTM)是精神分裂症中受损最严重的认知领域之一，也是预测疾病长期功能结果的最强指标之一。情节记忆力较好的患者也往往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会受到我们目前可用的治疗方法的影响，新的治疗方法还没有建立起来。目前的建议旨在确定精神分裂症患者情节记忆功能相对强弱的神经生物学机制，为新的治疗开发提供靶点。这项拟议的研究测试了这一新理论，即在新的学习情况下，精神分裂症患者参与背外侧前额叶(DLPFC)和海马区机制的能力尤其受损，这些机制是在形成和检索长期记忆的同时处理相互关系的信息所必需的。在记忆形成过程中，预计患者在使用强调工作记忆中项目之间关系的策略时会遇到困难(即DLPFC工作记忆(WM)控制缺陷)，也无法建立对项目之间的关系和它们所处环境的长期记忆(即海马体关系绑定缺陷)。相比之下，患者参与腹外侧额叶皮质(VLPFC)以维持西医中的个别项目的能力，以及他们参与周边皮质(PRC)以形成LTM中的个别项目表征的能力预计是完整的。在记忆提取过程中，患者被假设表现出类似的关系缺陷，提取更多地基于单个项目的记忆强度(即基于熟悉度的识别)，而较少基于对遇到项目的关系上下文的提取(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方面存在特定缺陷的假设，而他们的项目记忆是完整的。2)利用功能磁共振成像(FMRI)验证以下假设：精神分裂症患者的关系记忆缺陷与DLPFC和海马区的活动和连接性降低有关，而VLPFC和PRC的活动是完整的。3)探讨精神分裂症患者记忆成绩、DLPFC与海马区功能障碍及临床症状和功能障碍的关系。这项研究的成功完成将为精神分裂症患者LTM缺陷背后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特定的关系记忆缺陷，而不仅仅是一般注意力不集中、动机不佳或任务投入等引起的广泛性缺陷；将确定在哪些条件下存在被保留的认知功能区域，可用于补救努力；并将确定记忆障碍的临床、认知、神经和功能结果相关，可成为新药开发的目标和结果措施，以促进现有的认知增强临床试验。 与公共卫生相关：精神分裂症的特征是严重的记忆缺陷，损害日常心理社会功能，并限制长期结果。这项研究建议使用行为、功能磁共振和眼动实验来测试一种关于神经认知机制的新理论，该机制可以解释障碍中的记忆强弱，从而确定开发新的前认知药物的目标机制。

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.