Neural Mechanisms of Memory Dysfunction in Schizophrenia

描述(由申请人提供)：工作记忆(WM)和情景长期记忆(LTM)功能障碍是精神分裂症(SZ)的一个核心特征，它限制了心理社会功能，对目前的药物没有反应，在认知训练中只显示出轻微的改善，表明需要了解基本的神经机制来指导新治疗的开发。我们之前的研究和其他人的研究发现了SZ记忆强弱的特定模式，提出了一个双网络模型，在该模型中，背外侧前额叶皮质(DLPFC)和海马体(HI)记忆回路对将物品与特定空间或时间背景联系以支持回忆至关重要，而腹外侧额叶皮质(VLPFC)和周围皮质(PRC)记忆回路相对完整，而腹外侧额叶皮质(VLPFC)和周边皮质(PRC)记忆回路对于编码基于熟悉的提取项目信息至关重要。当前项目的目标是将这种双网络模型与基本的分子和神经候选机制联系起来。我们将使用一种集成了磁共振波谱(MRS)、脑电(EEG)和功能磁共振成像(FMRI)的创新多模式神经成像方法来测试中心思想，即SZ的DLPFC中存在GABA能抑制的破坏，这有助于减少先前研究和初步数据中观察到的theta振荡、DLPFC和HI fMRI损伤，以及不成比例的关系记忆缺陷。这种多模式成像方法将使用时间背景与项目记忆范式，最近在备受瞩目的健康个人研究中得到验证，将评估药物效果(服用药物和未服用药物的参与者数量相等)，并将调查先前观察到的与临床症状(组织紊乱和阴性症状)和心理社会功能(UPSA-B)的关系。将解决以下具体目标：目标1-评估健康对照组(HC)和SZ患者中项目和时间背景信息的WM和LTM；目标2-使用EEG识别与HC和SZ中项目和时间背景信息的WM维持和LTM编码相关的神经振荡；目标3-使用MRI评估HC和SZ中项目和时间背景信息LTM检索期间的GABA浓度和fMRI活动模式。通过将假想的神经生理机制与特定的记忆强弱联系起来，建议的研究避免了对SZ记忆功能障碍的普遍缺陷解释，确定了可以通过认知修复增强的相对强项，并在分子、生理和行为水平确定了记忆损害的生物标记物，可以指导新的治疗方法的开发。

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.