Neural Mechanisms of Memory Dysfunction in Schizophrenia

描述（由申请人提供）：工作记忆（WM）和情景性长期记忆（LTM）功能障碍是精神分裂症（SZ）的核心特征，其限制了心理社会功能，对当前药物无反应，并且仅显示出认知训练的适度改善，表明需要了解基本神经机制以指导新治疗的开发。我们以前的研究，以及其他人的研究，已经确定了SZ的记忆优势和劣势的特定模式，这表明了一个双网络模型，其中背外侧前额叶皮层（DLPFC）和海马（HI）记忆回路对于将项目与特定的空间或时间背景联系起来以支持回忆非常重要，而腹外侧前额叶皮层（VLPFC）和嗅周皮层（PRC）的记忆回路相对完整，这两个记忆回路对编码项目信息以支持基于熟悉性的提取很重要。当前项目的目标是将这种双神经元模型与基本的分子和神经候选机制联系起来。我们将使用一种创新的多模态神经成像方法，将磁共振波谱（MRS）、脑电图（EEG）和功能性磁共振成像（fMRI）整合在一起，以测试SZ中DLPFC中GABA能抑制的中断这一中心思想，这有助于减少θ振荡、DLPFC和HI fMRI损伤，以及在先前的研究和初步数据中观察到的不成比例的关系记忆缺陷。这种多模式成像方法将采用最近在健康个体的备受瞩目的研究中验证的时间背景与项目记忆范式，将评估药物效果（有相同数量的药物治疗和未治疗的参与者），并将调查之前观察到的与临床症状（混乱和阴性症状）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（HC）和SZ患者的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;目的3 -使用MRI评估在LTM检索HC和SZ中的项目和时间背景信息期间的GABA浓度和fMRI活动模式。通过将假设的神经生理机制与特定的记忆优势和弱点联系起来，拟议的研究避免了SZ记忆功能障碍的广义缺陷解释，确定了可以通过认知补救增强的相对优势，并确定了可以指导新治疗开发的分子，生理和行为水平上的记忆障碍生物标志物。

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.