Neural Mechanisms of Memory Dysfunction in Schizophrenia

精神分裂症记忆障碍的神经机制

• 批准号: 8796667
• 负责人: John D Ragland
• 金额: $ 51.6万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8796667
• 关键词: Address; Behavioral; Biological Markers; Chronic; Clinical; Cognition; Cognitive remediation; Data; Development; Disease; Electrodes; Electroencephalography; Episodic memory; Exhibits; Familiarity; Functional Magnetic Resonance Imaging; Functional disorder; Goals; Health Care Costs; Hippocampus (Brain); Impaired cognition; Impairment; Individual; Intervention; Learning; Link; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Measures; Memory; Memory impairment; Methods; Modeling; Molecular; Multimodal Imaging; Neural Inhibition; Participant; Patients; Pattern; Performance; Pharmaceutical Preparations; Physiological; Prefrontal Cortex; Quality of life; Relative (related person); Research; Retrieval; Schizophrenia; Short-Term Memory; Site; Spottings; Symptoms; Testing; Translating; Work; base; cognitive training; disability; gamma-Aminobutyric Acid; improved; innovation; long term memory; memory encoding; memory process; memory retrieval; network models; neural circuit; neuroimaging; neuromechanism; neurophysiology; novel; psychosocial; public health relevance; relating to nervous system; relational memory; research study; therapy development

DESCRIPTION (provided by applicant): Working memory (WM) and episodic long term memory (LTM) dysfunction is a core feature of schizophrenia (SZ) that limits psychosocial function, is unresponsive to current medications, and shows only modest improvements with cognitive training, demonstrating the need to understand basic neural mechanisms to guide development of new treatments. Our previous research, and that of others, has identified a specific pattern of memory strengths and weaknesses in SZ, suggesting a dual-network model in which dorsolateral prefrontal cortex (DLPFC) and hippocampal (HI) memory circuits important for relating items to a specific spatial or temporal context to support recollection is disproportionately impaired, whereas ventrolateral prefrontal cortex (VLPFC) and perirhinal cortex (PRC) memory circuits important for encoding item information in support of familiarity based retrieval are relatively intact. The goal of the current project is to link this dual- networ model to fundamental molecular and neural candidate mechanisms. We will use an innovative multimodal neuroimaging approach integrating magnetic resonance spectroscopy (MRS), electroencephalography (EEG) and functional magnetic resonance imaging (fMRI) to test the central idea that there is a disruption in GABAergic inhibition in the DLPFC in SZ, which contributes to the reduced theta oscillations, DLPFC and HI fMRI impairments, and disproportionate relational memory deficits observed in prior research and preliminary data. This multimodal imaging approach will employ temporal context versus item memory paradigms recently validated in high profile studies of healthy individuals, will assess medication effects (y having equal numbers of medicated and unmedicated participants), and will investigate previously observed relationships with clinical symptoms (disorganization and negative symptoms) and psychosocial function (UPSA-B). The following Specific Aims will be addressed: Aim 1 - Assess WM and LTM for item and temporal context information in healthy controls (HC) and people with SZ; Aim 2 - Use EEG to identify neural oscillations associated with WM maintenance and LTM encoding of item and temporal context information in HC and SZ; Aim 3 - Use MRI to assess GABA concentrations and patterns of fMRI activity during LTM retrieval of item and temporal context information in HC and SZ. By linking hypothesized neurophysiological mechanisms to specific memory strengths and weaknesses the proposed research avoids a generalized deficit explanation of memory dysfunction in SZ, identifies relative strengths that can be enhanced through cognitive remediation, and identifies biomarkers of memory impairment at the molecular, physiological and behavioral level that can guide new treatment development.

描述（由申请人提供）：工作记忆（WM）和情节长期记忆（LTM）功能障碍是精神分裂症（SZ）的核心特征（SZ），它限制了心理社会功能，对当前药物无反应，并且仅显示出适度的改进，通过认知训练，认知训练，认知训练，证明需要了解基本的神经机制来指导新疗法的发展。我们以前的研究以及其他研究已经确定了SZ中的记忆强度和劣势的特定模式，这表明了双网络模型，其中背侧外侧前额叶皮层（DLPFC）和海马（HI）记忆电路对于将特定项目与特定项目相关联重要支持回忆的空间或时间上下文受到不成比例的损害，而腹外侧前额叶皮层（VLPFC）和周围的皮层（PRC）存储器电路对于支持基于熟悉性的缩回的项目信息很重要。当前项目的目的是将这种双重模型与基本分子和神经候选机制联系起来。我们将使用创新的多模式神经影像学方法，整合磁共振光谱（MRS），脑电图（EEG）和功能磁共振成像（FMRI）来测试核心观念，即SZ中DLPFC中GABAergic抑制作用造成了损害在先前的研究和初步数据中观察到的tHETA振荡，DLPFC和HI FMRI障碍以及不成比例的关系记忆缺陷。这种多模式成像方法将采用时间上环境与项目记忆范式最近在健康个体的知名研究中验证，将评估药物效应（y具有相等数量的药物和未药物参与者），并将调查先前观察到的与临床症状（混乱和混乱和混乱和混乱的关系）负面症状）和社会心理功能（UPSA-B）。将解决以下具体目标：目标1-评估健康控制中的项目和时间上下文信息（HC）和SZ患者中的项目和时间上下文信息；目标2-使用脑电图来识别与WM维护和LTM编码有关HC和SZ中的时间上下文信息相关的神经振荡； AIM 3-使用MRI评估LTM在HC和SZ中的LTM检索和时间上下文信息期间fMRI活性的GABA浓度和模式。通过将假设的神经生理机制与特定的记忆强度和劣势联系起来，提出的研究避免了对SZ中记忆功能障碍的普遍缺陷解释，可以确定可以通过认知能力来增强的相对强度，并确定在分子，生理和行为层面上对生物损害的生物标志物来增强的强度这可以指导新的治疗发展。