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）的核心特征，它限制了心理社会功能，对当前药物无反应，并且在认知训练中仅显示出适度的改善，这表明需要了解基本的神经机制以指导新疗法的发展。我们之前的研究和其他人的研究已经确定了SZ的记忆优势和弱点的特定模式，提出了一个双网络模型，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）和周围皮层（PRC）的记忆回路相对完整，这些记忆回路对编码项目信息以支持基于熟悉度的检索至关重要。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。我们将使用一种创新的多模态神经成像方法，结合磁共振波谱（MRS）、脑电图（EEG）和功能性磁共振成像（fMRI），来验证SZ的DLPFC中gaba能抑制被破坏的中心思想，这有助于减少θ波振荡，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相关记忆缺陷。这种多模态成像方法将采用最近在健康个体的高调研究中得到验证的时间情境与项目记忆范式，将评估药物效果（有相同数量的服药和未服药的参与者），并将调查先前观察到的与临床症状（紊乱和阴性症状）和心理社会功能的关系（UPSA-B）。目标1 -评估健康对照（HC）和SZ患者的WM和LTM的项目和时间背景信息；目的2 -利用脑电图识别与WM维持和LTM编码相关的神经振荡；目的3 -使用MRI评估在HC和SZ的LTM项目和时间背景信息检索过程中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，本研究避免了对SZ记忆功能障碍的广义缺陷解释，确定了可以通过认知修复增强的相对优势，并在分子、生理和行为水平上确定了记忆障碍的生物标志物，可以指导新的治疗开发。

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.